A Journey through the Inter-Cellular Interactions in the Bone Marrow in Multiple Myeloma: Implications for the Next Generation of Treatments.

1. Introduction

Nowadays, it is widely accepted that the tumor microenvironment (TME) is a relevant component in tumors that modulates the response to cancer treatments affecting tumor progression. The TME consists of an extracellular matrix, a plethora of tumor cells, and a variety of non-tumor cells with complex interactions. These interactions, either through cell–cell contact or as soluble mediators, can accelerate tumor progression and the lack of response to cancer therapy [ 1 ]. Moreover, the knowledge of these interactions enables the development of non-immunotherapy [ 2 , 3 , 4 ] and immunotherapy strategies [ 5 , 6 , 7 , 8 , 9 ] in cancer patients.

Non-tumor cells in the TME, including endothelial cells, fibroblasts, and immune cells [ 7 ], modulate the responses to chemotherapy cancer treatments. For instance, chemotherapy agents that induce DNA damage, such as doxorubicin, trigger cytokine production by endothelial cells that decrease chemosensitivity of tumor cells to these treatments [ 10 ]. DNA-damaging agents also induce a senescence state in cells with the production of a senescence-associated secretory phenotype (SASP), a secretome rich in chemokines and growth factors that promote tumor progression [ 11 ]. Indeed, the secretion of SASP by endothelial cells in the TME includes IL6 secretion and chemoresistance development [ 12 ]. Tumor-associated macrophages (TAMs) with an M2-like phenotype provide a survival advantage to tumor cells in hypoxic conditions through IL6 receptor-mediated signals [ 13 ]; they protect tumor cells against paclitaxel, etoposide, and doxorubicin [ 14 ]. Moreover, platinum-based therapy supports monocyte differentiation to M2 macrophages, which associates with tumor progression [ 15 ].

Cellular components in the TME also influence the efficacy of radiotherapy treatments. Hence, radiotherapy activates fibroblasts, which become cancer-associated fibroblasts (CAFs). While some studies argue that CAFs promote tumor progression, others claim they are beneficial [ 16 , 17 ]. Thus, CAFs can secrete cytokines, such as IL32 that promote cancer cell invasion and metastasis [ 18 ]. However, CAFs in vivo depletion accelerates pancreatic cancer accompanied by epithelial-to-mesenchymal transition and enhanced T-regulatory (regs) cells that is reversed with anti-CTLA4 immunotherapy [ 19 ].

Immune cells and their secretome also shape the TME [ 1 ], impacting cancer progression and the efficacy of immunotherapy treatments [ 20 ]. For instance, tumor-infiltrating cells (TILs) in the TME are the basis for developing immunotherapy strategies based on immune checkpoint inhibition (ICI) that try to reactivate the tumor immune-surveillance activity of TILs [ 9 ]. Radiotherapy can promote tumor-specific immunity by activating dendritic cells (DCs) in the TME that support tumor-specific effector CD8 T cells [ 21 ]. Moreover, immunotherapy strategies based on the infusion of chimeric antigen receptor (CAR)-modified T cells have significantly improved the treatment of hematological malignancies [ 22 , 23 , 24 , 25 ]. However, in solid tumors, the barriers imposed by the TME [ 26 ] have delayed the development of efficient CAR-T cell therapies. Age also seems to play an essential role in the immune cells’ activity and, therefore, in immunotherapy. Thus, in hematological malignancies, pediatric patients with acute lymphoblastic leukemia (ALL) have achieved outstanding responses after treatment with CAR-T cells [ 22 ]. However, in adult patients with multiple myeloma (MM) [ 27 ], a disease where aging is a risk factor and where the TME is more relevant than in ALL, a proportion of patients end-up relapsing. In MM, the progression of the disease is drastically affected by the TME, either by soluble factors or cell–cell interactions in the bone marrow (BM) [ 28 ]. Moreover, relapses after administration of CAR-T cells [ 27 ], and the lack of efficacy of ICI therapies with significant toxicities in MM [ 25 ] might be partly explained by the impact of non-immune and immune cell interactions in the TME.

Here, we will take a journey through the BM, describing the interactions of plasma MM cells with cells of the non-hematological compartment to highlight the impact that these interactions have on the survival of tumor cells and the development of novel MM treatments. Moreover, we will describe the main differences found in the different immune cell subsets in the BM of MM patients that might lead to deficient tumor surveillance and failure of immunotherapy treatments in MM.

2. Impact of Interactions between Non-Hematological Cells and MM Cells in the BM

2.1. Extracellular Matrix (ECM)

MM is a hematologic malignancy characterized by clonal proliferation of plasma cells in the BM [ 29 ]. However, different trafficking events of MM cells allow them to reach distinct niches from the BM, re-circulate to the BM, and finally egress from the BM during the extramedullary stage of the disease [ 28 ]. When MM cells re-enter the BM, they use the BM sinusoids, where the interaction CXCR4/CXCL12 is critical to promote both MM cell homing and retention in the BM [ 30 ]. In the BM, MM cells will interact first with proteins in the ECM, a complex layer of proteins that serves as a scaffold for many cells. Interactions between MM cells and the ECM are required for cell proliferation, migration, and survival [ 31 ]. Specifically, CD138 and VLA-4 on MM cells directly interact with the ECM proteins, such as collagen type 1 and fibronectin. The binding of VLA-4 to fibronectin induces activation of nuclear factor-kB (NFkB), inducing tumor cell survival and cell adhesion-mediated drug resistance [ 32 ]. These interactions generate a welcome and growth-supporting environment that stimulates the dissemination of the malignant plasma cells and results in the upregulation of anti-apoptotic proteins and cell cycle dysregulation [ 33 ]. Strategies used in the clinic to disrupt these MM–ECM interactions and reduce cell adhesion-mediated drug resistance include the CXCR4 inhibitor AMD3100 or the proteasome inhibitor bortezomib, which downregulates VLA-4 on MM cells [ 34 ], leading to the de-adhesion of MM cells from the BM and turning them more sensitive to therapeutic agents [ 35 ]. However, although these agents can enhance the efficacy of treatments by disrupting these interactions, they also contribute to the mobilization of MM cells from the BM into the circulation, promoting extramedullary disease [ 36 ].

2.2. Control of the Stroma by BM Mesenchymal Stromal Cells (BM-MSCs)

In physiological conditions, the primary cell population in the BM stroma, known as bone marrow mesenchymal stromal cells (BM-MSCs), support the maintenance and differentiation of hematopoietic lineages, regulate bone homeostasis and contribute to the spatial delimitation of the endosteal and vascular niches [ 37 ]. However, in MM, BM-MSCs, as part of the BM microenvironment, play a crucial role in the pathology of the disease. Despite being at low proportions in the BM (0.01 to 0.001% of mononuclear cells) [ 38 ], BM-MSCs are the main population among BM stromal cells that interact with MM cells by direct cell–cell contact or through paracrine secretion of different pro-survival cytokines. Thus, for instance, binding VLA-4 on MM cells to VCAM-1 on BM-MSCs promotes activation of NFkB increasing MM cell survival and proliferation [ 39 ]. Moreover, the integrin lymphocyte function-associated antigen 1 (LFA-1) on MM cells and its transmembrane binding partner Mucin 1 (MUC1) bind to ICAM-1 in adjacent BM-MSCs, resulting in the activation of different pathways associated with poor prognosis and disease progression in patients [ 40 ]. The strong impact of the interactions with BM-MSCs in the physiology of MM cells and their acquisition of multidrug resistance phenotype justifies their consideration as targets for MM therapy. Indeed, some drugs have been developed to disrupt these interactions and tested in MM patients, such as Natalizumab, a recombinant humanized IgG4 monoclonal antibody (MoAb) which binds α4 integrin impairing the interaction VLA-4/VCAM-1 ( NCT00675428 ). Other promising approaches have been preclinically evaluated, such as the LFA-1 inhibitor LFA878 [ 41 ].

Soluble mediators are also required for MM plasma cell survival and proliferation in the BM. Thus, MM cells induce BM-MSCs to secrete cytokines that will be used for their benefit. Specifically, the main secreted cytokine is interleukin-6 (IL6), which is involved in MM growth, survival, migration, and drug resistance [ 42 ]. In turn, MM cells use IL6 to enhance the secretion of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Then, both VEGF and bFGF bind to their receptors on BM-MSCs, re-stimulating IL6 production [ 43 ]. Whereas inhibition of IL6 has not shown clinical benefit in MM [ 44 ], blocking of IL6 receptor with tocilizumab has shown efficacy in MM patients [ 45 ]. Furthermore, MM cell interactions with BM-MSCs cells are mediated through Notch pathways and Dickkopf-1 (DKK1), which induce the secretion of IL6, VEGF, and insulin-like growth factor (IGF-1) in BM-MSCs [ 46 , 47 ]. Moreover, MSC-derived exosomes contain the long intergenic noncoding RNA LINC00461, which promotes MM cell proliferation and suppresses the beneficial effect of dexamethasone treatment. Indeed, the knockdown of LINC00461 enhances the beneficial impact of dexamethasone in preclinical studies [ 48 ].

B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) are additional mediators with a protective effect on MM cells [ 49 ]. BAFF is a member of the tumor necrosis factor (TNF) family expressed on the surface of BM-MSCs and as a soluble form. BAFF stimulates B cell growth, and ligation of BAFF leads to increased proliferation and survival of MM cells [ 50 ]. APRIL is a secreted protein by BM-MSC that binds to B-cell maturation antigen (BCMA) and to transmembrane activator and calcium-modulator and cyclophilin ligand (TACI) on MM cells [ 51 ]. Therefore, APRIL-based CARs target MM cells expressing either BCMA or TACI with high efficacy at pre-clinical levels [ 52 ]. Moreover, BM-MSCs also protect MM cells against the lytic machinery of CAR-T cells [ 53 ].

Another member of the TNF family involved in this stromal training is TNFα, which induces the expression of adhesion molecules, such as LFA-1, ICAM-1, VCAM-1, and VLA-4 on MM cells, as well as ICAM-1 on BM-MSCs, resulting in increased binding of MM cells to BM-MSCs and further enhancing IL6 secretion [ 54 ]. These paracrine loops are critical for maintaining the constant growth of MM cells through the activation of different signaling pathways. In addition, MM cell interactions with BM-MSCs, added to the senescent status of cells in the BM in MM, further enhance the secretion of cytokines, chemokines, and soluble factors secreted by BM-MSCs to the BM milieu, which induce further MM proliferation and survival. TNFα, crucial in inflammation, is related to bone resorption and enhanced in MM patients. Thus, targeting TNFα could improve MM responses to treatments [ 55 ]. However, reports in inflammatory diseases suggest that anti-TNF-α inhibitors enhance the risk of having future hematological malignancies [ 56 ].

In summary, these interleukins and growth factors secreted by BM-MSCs cause tumor growth and drug resistance, limiting current MM treatments’ impact. Indeed, they are promising targets for developing anti-MM therapies that avoid the negative effect of BM-MSCs on dexamethasone treatment [ 48 ], on CAR-T cell therapies [ 53 ], or the negative impact of IL6 secretion. Thus, tocilizumab, an anti-IL6R [ 57 ], BHQ880, a monoclonal antibody against DKK1 [ 58 ], or tabalumab, a potent and selective fully human IgG4 MoAb with neutralizing activity against membrane-bound and soluble BAFF [ 59 ] are strategies that could be added to MM treatment.

2.3. Osteoclast/Osteoblast Imbalance in the Endosteal Niche

As previously mentioned, MM cells not only interact with the stromal compartment they also alter the endosteal and vascular niches in the BM. In the endosteal niche, healthy bone remodeling in the BM is maintained by a balance between bone formation (osteoblastogenesis) versus bone degradation (osteoclastogenesis). However, MM cells alter this dynamic balance, enhancing bone resorption to enable space for MM proliferation, causing the osteolytic lesions characteristic of myeloma bone disease (MBD) in around 80–90% of MM patients [ 60 ]. The negative impact of MBD on patient survival, quality of life, and public health costs has led to the development of different approaches to block MM-endosteal niche interactions. Strategies for patients to treat and avoid MBD have recently been reviewed [ 61 ]. Here, we describe which interactions of MM cells with cells in the endosteal niche, including BM-MSCs and other bone populations, such as osteoclasts and osteoblasts, accelerate MBD.

MM cells, through different mechanisms, upregulate osteoclast activity and differentiation resulting in imbalanced bone resorption, causing the osteolytic lesions of the MBD [ 62 ]. Specifically, MM cells secrete macrophage inflammatory protein-1α (MIP1α) and MIP1β that directly activate osteoclast formation and activity [ 63 , 64 ]. In turn, osteoclasts secrete IL6 to stimulate their self-proliferation and the proliferation of MM cells [ 65 ]. This interaction upregulates Chondroitin synthase 1 (CHSY1), which induces Notch signaling promoting MM cell survival and stimulating the recruitment of osteoclast precursors to increase bone resorption [ 66 ]. Macrophage-colony stimulating factor (M-CSF) and receptor activator of NFkB (RANK) ligand (RANKL) are additional factors required for osteoclast differentiation. Osteocytes produce RANKL, which promotes osteoclast activity through binding to RANK on osteoclastic lineage cells [ 67 ]. Nevertheless, MM cells’ interaction with BM-MSCs leads to the secretion of RANKL by BM-MSCs, further stimulating osteoclast activation and differentiation and enhancing bone lysis. This interaction also leads to the production of cytokines by BM-MSCs, such as IL6, which further promotes osteoclast growth [ 68 ]. In this way, amino-bisphosphonates have been administered in MM patients as first-line therapy for MBD due to their capacity to inhibit osteoclast activity [ 69 ]. Moreover, Denosumab, a fully human monoclonal antibody against RANKL, has also shown clinical benefit in MM patients [ 70 ]. Denosumab inhibits the development and activity of osteoclasts, decreases bone resorption, and increases bone density [ 71 ].

On the other hand, MM cells prevent osteoblast progenitor cell maturation and inhibit osteoblast activation, to continue impairing bone formation. Direct cell–cell interactions of MM cells through binding to VCAM-1 on osteoblast progenitors downregulate RUNX2 activity, essential for osteoblast differentiation [ 72 ]. Moreover, osteoblasts and BM-MSCs produce osteoprotegerin (OPG), which prevents the development of bone alterations caused by osteoclast/osteoblast imbalance. However, the binding of VLA-4 on MM cells to VCAM-1 on BM-MSCs decreases OPG secretion, forcing the balance in favor of osteoclasts and bone degradation [ 73 ]. Disrupting this VLA-4/VCAM-1 interaction with monoclonal antibodies, such as Natalizumab, could prevent bone lysis in MM patients, as described in preclinical models [ 74 ]. On the other hand, BHQ880, the DKK1-neutralizing antibody, can increase osteoblast differentiation, blocking the negative effect of MM cells on osteoblastogenesis and reducing IL6 secretion in MM patients [ 75 ].

2.4. Angiogenesis Promotion in the Vascular Niche

During the development of MM, an alteration in the neovascularization process occurs that affects the vascular niche. Neovascularization is the formation of new vessels from existing ones through endothelial cells (angiogenesis) or from endothelial precursors (vasculogenesis). Interactions between plasma cells and the BM microenvironment can modify this biological process [ 76 , 77 , 78 ].

Angiogenesis in cancer involves an early balanced avascular phase that gives rise to an uncontrolled and unlimited in-time vascular phase [ 79 ]. In the context of MM, Rajkumar et al. demonstrated that the BM microvascular density is increased in MM patients [ 80 ]. In this environment, the accumulation of MM cells in the BM generates hypoxic tumors highly expressing hypoxia-inducible factor-1 alpha (HIF-1α). HIF-1α will upregulate angiogenesis to deliver oxygen and nutrients and remove catabolites [ 81 ]. Different cytokines control angiogenesis, such as VEGF, fibroblast growth factor-2 (FGF-2), and hepatocyte growth factor (HGF). In MM, MM plasma cells become CD45-negative and produce VEGF [ 82 ]. Moreover, endothelial cells in the BM of MM modify their phenotype, expressing surface receptors related to angiogenesis, such as VEGFR-2 and Tie2/Tek, and increased expression of the β3-integrin and endoglin [ 83 ]. This differentiated phenotype in endothelial cells of the BM enhances MM cell interaction with the new-formed blood vessels and favors the entry and dissemination of MM cells into the circulation. This angiogenic phenotype in MM cells can also be induced by oncogenes, such as C-MYC, C-FOS, C-JUN, and ETS-1, which become active as a consequence of the genetic instability and immunoglobulin translocations in MM [ 84 ].

On the other hand, the differentiation of endothelial progenitors termed angioblasts during embryogenesis causes the development of the vascular system, known as vasculogenesis [ 85 ]. Studies suggest that vasculogenesis is responsible for the neovascularization in the BM in MM [ 86 , 87 ]. Indeed, endothelial markers such as VIII-related antigen (FVIII-RA), vascular endothelial-cadherin (VE-cadherin), VEGFR-2, TIE/Tek, and CD133 are expressed in endothelial cells of the neovessel wall [ 88 ]. Moreover, interactions of MM cells with BM-MSCs in the BM also impact vasculogenesis. Thus, MM cells stimulate BM-MSCs in the vascular niche to secrete HGF, VEGF, and IL8, further inducing neovascularization [ 89 ]. In turn, endothelial cells in MM will produce IGF1 and IL6 to promote MM cell growth, causing an autocrine loop in endothelial cells, which will enhance their production of VEGF, platelet-derived growth factor (PDGF), Ang-1, HGF, and IL1 to promote angiogenesis constantly [ 90 ].

The relevance of angiogenesis in the development of MM has led to the development of different treatments targeting this process. For instance, amino-bisphosphonates that inhibit osteoclasts also present anti-angiogenic activities and are administered in MM patients as supportive therapy for bone disease [ 69 ]. Ria et al. reviewed different strategies in MM mainly based on VEGF inhibition, such as monoclonal antibodies anti-VEGF (Bevacizumab) [ 91 ]. However, the addition of bevacizumab to anti-MM therapies did not result in a significant improvement in the outcome of patients [ 92 , 93 ]. Derivatives of quinolone and quinazoline, which inhibit a variety of tyrosine kinases, including VEGFRs, EGFR, and PDGFR have also been tested in MM patients. Despite their in vitro activity and reduced plasma levels of VEGF in treated MM patients, no responses or clinical benefits were achieved [ 94 , 95 ]. These disappointing results inhibiting a single proangiogenic cytokine could be related to the role played by hypoxia and other active pro-angiogenic pathways in the BM microenvironment, and greater efficacy could be feasible with drugs that simultaneously block multiple cytokines. Moreover, immunomodulators (IMIDs), such as thalidomide or lenalidomide, have revealed anti-angiogenic activity and inhibition of the secretion of angiogenic cytokines in MM patients [ 96 , 97 ].

To summarize, interactions between MM cells and cells that do not belong to the hematological BM compartment form a feedback loop that leads to bone destruction, angiogenesis, and tumor expansion in the BM. Unraveling these interactions has allowed the development of novel treatments for MM patients combining different strategies to block several molecules simultaneously. The most pertinent inter-cellular interactions, their impact, and the possible options of treatments are summarized in Figure 1 and Table 1 . However, as we will explain in the next section, immune cells also play a relevant role in MM progression.

3. Impact of Interactions between Immune Cells and MM Cells in the BM of MM Patients

On the other hand, immune cells make up the hematological compartment of the BM, where the crosstalk between MM plasma cells and immune cells, from both myeloid and lymphoid lineage, plays a critical role in MM growth and maintenance. However, while non-hematological cell populations are partners that MM cells use for their benefit, the immune cell compartment is naturally composed of anti-tumor cells involved in tumor immunosurveillance [ 149 ]. However, MM cells create an immunosuppressive microenvironment and evade the immune system, a dynamic process encompassing multiple aspects of tumor cell–immune cell interactions [ 150 ] that favors MM proliferation and resistance to treatments [ 151 ]. In addition, the immune cells’ plasticity and capacity to polarize to different subsets enable the survival of normal and malignant plasma cells in the BM [ 152 ]. Another level of complexity comes with the deterioration of the immune system associated with aging, where MM represents an elderly population. Moreover, the accumulation and/or recruitment of immunosuppressive lymphoid and myeloid cells within the BM is another powerful mechanism during myelomagenesis [ 153 ].

This section describes relevant aspects of the different immune cell subsets in MM patients related to their inability to control MM progression. These interactions and how to avoid their detrimental impact are summarized in Figure 2 and Table 1 .

3.1. Effector CD8 T Lymphocytes

The potential anti-MM activity of T cells in MM was suggested in the past with the observation that levels of CD3, CD4, CD8, and CD19 cell subsets in MM are associated with response to chemotherapy and survival [ 154 ]. Thus, the presence of T cell clones in MM associates with prolonged overall survival suggesting their anti-tumor activity [ 155 ]. Indeed, tumor-infiltrating lymphocytes (TILs), defined as the lymphocytic cell populations present in tumors, can be used to design adoptive cellular immunotherapy strategies [ 156 ]. In MM, TILs are defined as marrow-infiltrating lymphocytes (MILs). Adoptive transfer of MILs in MM patients demonstrated a direct correlation between tumor specificity of the MILs with clinical outcomes. Of interest, compared to peripheral blood (PB) lymphocytes, MILs show increased expression of CXCR4, which through CXCL12/CXCR4 could facilitate the trafficking of MILs to the BM [ 101 ]. An interesting approach to enhance the trafficking of MILs could be to modify them to over-express CXCR4 [ 104 ]. In MM patients receiving MILs, CD8 T cells are the main cytotoxic T cell subset. It was observed that a central memory (CM) phenotype in CD8 T cells of MILs at baseline was associated with achieving complete responses (CR), whereas patients with disease progression had a higher frequency of terminally differentiated effector T cells at baseline [ 101 ]. An approach to avoid terminally differentiated MILs could be adding a PI3K inhibitor during the production of MILs, that in CAR-T cells has shown efficacy in reducing the proportion of highly differentiated or senescent T cells [ 105 ].

Moreover, CD8 T cells can become exhausted due to prolonged antigen stimulation [ 157 ]. Exhausted T cells express immune checkpoint receptors, including programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), LAG-3, or T cell immunoglobulin and ITIM domain (TIGIT) that interact with their ligands PD-L1, CD80/CD86, MHC-II, and CD155, respectively, on tumor cells [ 102 , 103 ]. This interaction is disrupted with immune checkpoint inhibitors (ICI) and restores the anti-tumor activity of exhausted T cells [ 102 , 103 ]. However, despite the success in malignancies such as melanoma [ 158 ], ICI causes adverse side effects [ 159 , 160 ], and targeting the PD-1/PD-L1 axis has not offered any clinical benefit in MM [ 106 ], showing high toxicity that led to the halting of different clinical trials [ 25 ].

Of interest, anti-PD1 therapy acts on a specific subpopulation of exhausted CD8 TILs termed “progenitor exhausted” cells that retain poly-functionality, persist long term, and differentiate into “terminally exhausted” TILs. Progenitor exhausted CD8 TILs respond to anti-PD-1 therapy and control tumor growth [ 161 ]. T cells in MM are highly differentiated [ 162 ], which might explain the lack of success in ICI studies. Indeed, within the PD-1 positive population of MILs in MM, only the subset of less differentiated CM T cells are responsive to anti-PD-1, and terminally exhausted T cells associate with worse clinical outcomes after PD-1 inhibition [ 163 ]. In addition, the lack of expression of PD-1 in CD8 T cells in newly diagnosed MM patients could also explain the lack of efficacy of the disruption of PD-1/PDL-1 interaction, being TIGIT the most frequent immune checkpoint receptor expressed on T cells [ 100 ]. Indeed TIGIT targeting has shown benefits in pre-clinical models of MM [ 100 ].

3.2. CD4 T Cell Subsets

During MM progression, an alteration in the number and proportion of the different T cell subsets occurs. Specifically, a reduced CD4/CD8 ratio, with lower number of CD4 T cells and Th2 cells is observed [ 107 ]. Moreover, IL6 secretion by MM cells [ 164 ] and by activated CD3 T cells in MM inhibits the polarization of naïve CD4 T cells into Th1 cells enabling tumor escape [ 108 ]. Immunotherapy strategies to obtain a product with an optimized CD4/CD8 T cell ratio [ 110 ] could improve this imbalance observed in MM. Indeed a higher CD4/CD8 ratio in the leukapheresis products used to generate CAR T cells in MM correlates with higher responses [ 111 ].

Within the CD4 population, regulatory T cells (T-reg cells) are characterized by FOXP3 expression [ 165 ]. T-regs have an important immunosuppressive activity towards antigen-presenting cells (APCs) and effector T cells by direct cell–cell contact or soluble mediators that promote immunological tolerance [ 166 ]. A variety of studies show that T-regs are enhanced in different types of cancers and related to tumor progression, including hematological malignancies [ 167 ]. However, there are conflicting results concerning their number and function in MM [ 168 ]. Thus, some studies describe elevated frequencies of functional T-reg cells in newly diagnosed and relapsed patients compared to healthy volunteers [ 169 ], while others reported a reduction in their number [ 170 , 171 ], being these T-reg cells dysfunctional [ 170 ]. Although there are few studies of T-regs comparing the BM to PB in MM, published reports show that the frequencies of T-regs in both departments are similar and that increased numbers of T-regs in the BM correlate with shorter time to progression and reduced survival [ 112 , 113 ].

The suppressive activity of T-regs in MM has been demonstrated in different studies via IL10 and TGFβ secretion that inhibit dendritic cells and block CD4 T cell-mediated generation of CD8 T cell cytotoxic activity [ 115 ]. Inducible T cell co-stimulator (ICOS) and CTLA-4 and expressed by T-regs are involved in their suppressive function [ 116 ]. Indeed, MM cells can directly generate functional T-reg cells contact-dependent through ICOS/ICOS-L. These T-regs can be inhibited with anti-ICOS-L MoAb [ 114 ]. In MM patients receiving MILs, the baseline percentage of T-regs was lower in patients who achieved a CR compared to those with disease progression. However, on day 360, the percentage of T-regs was normalized, reaching similar levels in all groups, with the CR patients showing the greatest increase [ 101 ].

In MM, treatment with talquetamab, a bispecific mAb against the G protein-coupled receptor (GPRC5D), expressed on MM cells, enhanced the anti-MM activity of CD4 conventional T cells but also of T-reg cells. However, T-reg cells presented lower anti-MM activity than conventional CD4 T cells, and seemed to ameliorate the activity of CD4 T cells with decreased production of IFNγ, TNFα, and IL2 [ 109 ].

On the other side, some reports demonstrate that higher numbers of T-regs in tumors associate with better prognosis in patients [ 172 ], suggesting that the exact prognostic significance of T-regs cells is still unclear, and further studies need to be done. For instance, preclinical studies based on a transient T-reg depletion have demonstrated immune control of MM and prevented disease progression [ 117 ].

Th17 cells are pro-inflammatory CD4 T cells that share a common precursor with T-reg cells, where different cytokines will promote the differentiation into one cell subtype or another [ 173 ]. Thus, TGFβ favors the formation of T-reg cells. However, in the presence of IL6, IL21 expression is enhanced, activating downstream signaling pathways that, with TGF-β, lead to the differentiation of Th17 cells [ 118 ]. In addition, Th17 and T-reg cells can polarize each other [ 173 ]. Th17 cells promote MM growth [ 119 ] and cause osteoclast-dependent bone damage [ 174 ]. Indeed, Th17 cell levels increase further in refractory disease [ 175 ] and MBD [ 176 ]. Moreover, IL17 production, due to an increased Th17 cell number, induces osteoblast cell death through pyroptosis with the release of IL1β [ 120 ] and cooperates with RANKL to further activate osteoclasts enhancing tumor growth and promoting MBD in MM [ 119 ]. Newly diagnosed MM patients present a higher number of Th17 cells and IL17 in serum, with decreased T-reg cells. Thalidomide treatment normalized the ratio of Th17 and T-reg cells in PB [ 121 ]. Indeed, the efficacy of MoAbs targeting IL17 has been assessed successfully at pre-clinical stages to treat MM [ 122 ].

3.3. The Impact of Age in T Lymphocytes in MM

The lack of efficacy of ICI in MM has suggested that other dysfunctionalities in T cells might be more relevant in MM, such as the presence of T cell “immunosenescence”. MM is a disease related to the elderly, and the immune system is highly impacted by age. Specifically, “immunosenescence” refers to the deterioration of the immune system that affects T cells, macrophages [ 177 ], and natural killer (NK) cells [ 178 ], leading to dysfunctional immune responses. In T cells, chronic viral infections, inflammatory diseases, a replacement of BM cellular components by adipocytes, and a thymic involution occurring with aging cause immunosenescence. Immunosenescence is characterized by a loss of the naïve and stem cell memory (SCM) T cell compartments as they differentiate, producing an accumulation of oligo-clonal memory and pro-inflammatory effector T cells that present shorter life and lower proliferative capacity [ 179 , 180 , 181 , 182 ]. Immunosenescence also reduces the capacity of T-reg cells to suppress self-reactive T cells and preserve immune homeostasis [ 180 , 181 ]. Moreover, T cell immunosenescence is accelerated with chemotherapy treatments [ 124 ] and after therapy with ICIs [ 125 ]. In general, most studies agree that immunosenescent T cells lose the naïve CD8 and CD4 T cell compartment, with loss of CD27 and CD28, increased expression of CD57, KLRG1, and PD-1, and secretion of large amounts of IFNγ and TNFα, IL2, IL4, IL10, and IL6 [ 11 , 183 ]. In MM, a higher number of immunosenescent T cells than healthy donors have been described [ 162 ] with low proliferative capacity and expression of CD57, KLRG1, CD160, CD28 − , PD1 low, and CTLA4 low [ 123 ]. Indeed, adoptive cell therapy with MILs in MM showed that the presence of less differentiated CM CD8 T cells correlated with achieving complete responses [ 101 ]. Moreover, the pro-inflammatory phenotype of immunosenescent T cells might explain the high number of adverse events observed in MM patients treated with ICIs [ 25 ].

In addition, immunotherapy based on administering CAR-T cells has achieved outstanding responses in pediatric patients, where CAR-T cells persist over the years in PB as guardians [ 22 ]. However, in MM, patients relapse despite achieving complete responses with a lack of persistence of CAR-T cells [ 27 ]. The presence of T cell immunosenescence in MM might partly explain the lack of persistence of CAR-T cells and suggest novel strategies to reverse T cell immunosenescence. The reversal of T cell immunosenescence is a field in development. Different approaches are being tested, including the recombinant growth hormone, that in healthy donors reversed immunosenescence partially with the regeneration of the thymus, a decline in the PD-1 positive CD8 T cells, and an increase in the naïve CD4 and CD8 T cells [ 184 ].

Cytokines also influence the differentiation of T cells. In this regard, the production of CAR-T cells and MILs provide a window to add different cytokines and compounds that modify the immunosenescence state of T cells that patients receive. Thus, IL-7, through binding to its receptor IL-7Rα, promotes the differentiation of naïve T cells into effector T cells [ 185 ]. Indeed, the addition of IL7 to IL15 during the production of CAR-T cells for MM accelerated the differentiation of CAR-T cells leading to a shorter CAR-T cell persistence in vivo in preclinical models. However, the production of CAR-T cells with IL15 obtained a product less differentiated that demonstrated the highest in vivo persistence compared to IL2 and the combination of IL7 and IL15 [ 126 ].

Kinases also regulate T cell senescence, and their inhibition has a high potential to avoid immunosenescence. Thus, inhibition of p38-MAPK in CD4 T cells enhances their survival after TCR activation [ 186 ]. Moreover, sestrins bind to and coordinate Erk, Jnk, and p38 MAPK activation in T cells within a complex termed sMAC. Compared to the inhibition of individual MAPKs, sestrin ablation in T cells from old humans disrupted the sMAC complex restoring immune function and antigen-specific functional T cell responses [ 127 ]. mTOR pathway is also involved in differentiating naïve CD4 + T cells into Th1 or Th17 cells T cells [ 187 ]. Thus, in older individuals, mTOR inhibitors, such as rapamycin or everolimus, have improved their immune function [ 188 ]. However, rapamycin also suppresses the anti-inflammatory effects of glucocorticoids in human monocytes and myeloid dendritic cells [ 189 ]. Inhibition of PI3K during the production of CAR-T cells for MM also provides a less differentiated product associated with a higher duration of response [ 105 ]. Adding these compounds only during the production of T cells that patients will receive will avoid the side effects observed after in vivo administration of these drugs.

3.4. NK Cells

NK cells are anti-tumor and anti-microbial cells of the innate immune system equipped with a wide array of activating and inhibitory receptors that activate or inhibit their activity through different mechanisms such as granzyme and perforin release, death receptor pathways, and release of additional pro-inflammatory molecules [ 137 , 190 , 191 , 192 , 193 ]. There are two main populations of NK cells in PB, the mature and cytotoxic NK CD56 dim and the immature and immunoregulatory CD56 bright NK cells [ 137 , 192 ]. Their anti-tumor activity and potential as an allogeneic source of immune cells have made NK cells an attractive target for immunotherapy in different malignancies, including MM [ 137 , 194 ]. A recent meta-analysis study in solid tumors showed that NK cell infiltration associates with increased overall survival in cancer patients. In detail, NK infiltration is more common in earlier stage and higher-grade tumors. Moreover, infiltrating NK cells in intraepithelial regions impacts survival more than infiltrating NK cells in the adjacent stroma [ 195 ].

NK cells recognize MM cells through activating receptors, including NKG2D, NKP30, 2B4, NKp80, or DNAM-1, which interact with their ligands in MM cells [ 137 , 190 ]. In newly diagnosed MM patients, the frequency of NK cells in PB does not differ from healthy donors [ 196 ]. However, NK cells in MM impair their cytotoxic activity with decreased expression of the activating receptor CD161 and increased expression of the inhibitory CD158a receptor [ 196 ]. In addition, MM cells downregulate or block NKG2D and NKp80 on NK cells, inhibiting their activity [ 128 ]. NK cells also express PD-1, that in MM patients is up-regulated and interacts with PD-L1 on MM cells [ 129 ]. BM stromal cells-derived IL6 inhibits NK cell activity [ 131 ] and induces PD-L1 expression in MM cells, impacting the anti-MM activity of NK and T cells [ 132 , 133 ]. Moreover, MDSCs, through tumor-derived IL1β, impair NK cell development and activity [ 134 ]. In addition, the expression of chemotactic factors and their receptors in the BM of MM affect the attraction of immune cells. Specifically, NK cells express CXCR3 to enable migration to the BM when required. During MM progression, chemokine ligands involved in the migration of NK cells are imbalanced, including increased levels of CXCL9 and CXCL10 and decreased levels of CXCL12. Moreover, a down-regulation of CXCR3 on NK cells occurs. Altogether drives NK cells outside the BM, weakening their anti-MM activity in the BM [ 135 ]. Therefore, altered interactions of NK cells with MM cells impair NK cell anti-tumor activity and are targets for developing strategies that reestablish the anti-MM response of NK cells. Many approaches have been proposed to improve NK cell activity [ 136 , 137 ]. These strategies could be the combination of NK cells with IMiDs and MoAbs that activate antibody-dependent cell cytotoxicity (ADCC) of NK cells. For instance, Daratumumab (anti-CD38), VIS832 (anti-CD138), and Dacetuzumab (anti-CD40) have demonstrated potential in preclinical studies. Bispecific and trispecific killer engagers (BiKEs/TRiKEs) also can redirect NK cells to tumor cells. Antibody recruiting molecules (ARMs) bind a tumor-associated antigen with endogenous IgG that will induce NK-mediated ADCC. NK cell activators, such as ALT-803, an IL-15 superagonist, stimulate NK cells and T cells, and finally, CAR-NKs targeting SLAMF7, CD138, or NKG2D ligands MM antigens have demonstrated pre-clinical efficacy [ 136 , 137 ].

In addition, decidual NK (dNK) cells represent a transient population present during the first months of pregnancy. dNK cells are CD56 bright and highly angiogenic through the production of proangiogenic factors, including VEGF, PlGF, CXCL8, IL10, and angiogenin [ 197 , 198 , 199 ]. It has been suggested that the recruitment of conventional CD56 bright PB-NK cells could contribute to their origin [ 200 , 201 ]. This angiogenic or “nurturing” role of dNK cells required during early pregnancy presents homologies to the angiogenic processes during tumor progression. In this regard, in relapsed/refractory and newly diagnosed MM patients, the CD56 bright NK cell subset, highly activated, is the prevailing NK cell subset in both BM and PB, being these differences more pronounced in the BM [ 130 ]. Therefore, further studies in MM patients should add additional markers to characterize better a possible angiogenic activity of CD56 bright NK cells detected in the BM of MM patients. Of interest, in vitro expanded NK cells administered in immunotherapy acquire a CD56 bright phenotype [ 202 , 203 ]. Thus, a possibility to improve clinical studies that infuse expanded NK cells in MM patients could be the previous selection of CD56 dim mature NK cells.

3.5. Regulatory B Cells

B-reg cells represent another essential immunosuppressive arm in the adaptive immune system that is affected by their interaction with MM cells. B-reg cells maintain immune tolerance and suppress autoimmune and inflammatory responses through secretion of IL35, TGFβ, and IL10, as well as expression of inhibitory molecules, such as PD-L1 [ 204 ]. In healthy donors, IL10 secretion of B-reg cells suppresses CD4 T cell proliferation and the release of IFN-γ and TNF-α by CD4 T cells, inhibits CD4 T cell differentiation into Th1 and Th17 cells, and favors CD4 T cell polarization into T-regs [ 138 ]. In the TME, tumor-released autophagosomes induce this B-reg population [ 205 ]. Despite their poorly described role in MM, B-reg cells have become essential players increasing during the initial stages of MM and head for extinction in relapsed or refractory MM [ 206 ]. Thus, newly diagnosed MM patients have no differences in PB B-reg cells compared to healthy donors. However, B-reg cells accumulate in the BM of newly diagnosed MM patients rather than in PB, where MM cells promote the survival of B-reg cells. Moreover, B-reg cells in PB and BM are higher at MM diagnosis than after response to therapy, and, finally, at relapse, they are too low to be detected. Moreover, MM B-regs avoid NK-ADCC against MM cells [ 139 ]. Despite the relevant role of B-reg cells in the progression of MM, strategies to target them in the clinic have not been described yet. Novel research to decipher cellular interactions of B-reg cells with other cells and how B-reg cells exert their suppressive activity is required first to foresee the possible implications of their targeting.

3.6. Tumor-Associated-Macrophages (TAMs)

Tumor-associated-macrophages (TAMs) abundant in the MM microenvironment, can protect MM cells from chemotherapy-induced apoptosis and exert anti-tumor activity [ 207 , 208 ]. Even though macrophages present high plasticity, they are traditionally classified into: (1) M1 activated macrophages with anti-tumor activity that secrete pro-inflammatory cytokines; or (2) the alternatively activated M2 macrophages with immunosuppressive activity. Indeed, several clinical studies in MM patients have associated a high infiltration of M2 macrophages in the BM with poor prognosis and poor response to current treatments, while patients with increased infiltration of M1 macrophages showed better outcomes [ 209 ]. M1/M2 polarization will rely on signals present in the environment. Thus, pro-inflammatory cytokines promote M1 differentiation, and immunosuppressive ones drive the differentiation towards an M2 phenotype [ 210 ]. MM cells influence the phenotype and recruitment of macrophages in the BM. Thus, CXCL12 production by MM cells and BM-MSCs increases monocyte recruitment through the CXCL12/CXCR4 axis and induces M2 macrophage polarization. These CXCR4-M2-educated macrophages are grown in the BM of MM compared to healthy controls, support MM cell proliferation, protect them from chemotherapy, and suppress T-cell proliferation and activity [ 140 ]. Of interest, MM cells secrete extracellular vesicles (EVs) that polarize recruited monocytes to an M2 phenotype with subsequent release of M2-associated cytokines such as IL6, IL10, IL8, and TNFα that promote tumor proliferation. Circulating miR-16 in serum impairs these events. Indeed, high miR-16 levels associate with prolonged survival in MM patients [ 211 ]. Moreover, soluble secreted forms of M2 macrophage receptors, such as CD206 and CD163, and chemokines like CCL2, have been proposed as biomarkers for disease progression, prognosis, and treatment response [ 141 , 142 ]. Moreover, macrophages directly affect immune evasion using their macrophage immune checkpoint. The binding of CD47 in the membrane of MM cells to signal-regulatory protein alpha (SIRPα) receptor on the surface of macrophages leads to downstream signaling within the macrophages, resulting in inhibition of phagocytosis activity [ 143 ].

The relevance of macrophages in MM is evidenced by increasing strategies used in preclinical and clinical studies to counteract their supportive role in MM progression. As mentioned, the CXCR4/CXCL12 axis contributes to MM cell adhesion and migration and promotes monocyte recruitment and differentiation towards a proangiogenic and immunosuppressive M2-like phenotype. In preclinical studies, the inhibition of CXCR4 significantly suppressed monocyte recruitment to the BM [ 140 ]. For that reason, analyzing the impact of AMD3100 (CXCR4 inhibitor) on macrophages in MM patients could reveal positive results. Once in the BM, depletion of BM resident macrophages is a strategy to reduce macrophage tumor support with promising preclinical results, proving that macrophage depletion can limit MM disease burden [ 144 ]. Other targeted therapies block the pro-tumor functions of TAMs, reprogramming them to reduce their immunosuppressive M2 phenotype and promote M1 phenotype. Currently, the most common approach for targeting macrophages involves inhibiting the CSF1 receptor (CSF1R), which regulates the migration, differentiation, and survival of macrophages and their precursors [ 145 ]. In MM, a recent preclinical study has demonstrated a significant reduction in tumor burden following treatment with the anti-CSF1R antibody [ 212 ], suggesting that targeting macrophages, via CSF1R, in combination with standard therapies, may be a promising therapeutic strategy in MM. Finally, targeting immune checkpoints in macrophages has been an emerging topic [ 213 ]. Currently, some clinical studies aim to inhibit the CD47-SIRPα immune checkpoint using various strategies, including anti-CD47 antibodies (SRF231: NCT03512340 and AO-176: NCT04445701 ) or SIRPα-IgG1 Fc fusion proteins (TTI-621: NCT02663518 and TTI-622: NCT03530683 ). In general, TAM-targeting therapy represents a promising treatment for MM patients and could improve current MM cell therapies, overcoming unresponsiveness and drug resistance.

3.7. Myeloid-Derived Suppressor Cells

(MDSCs) are a heterogeneous subset of immature myeloid progenitor cells that inhibit innate and adaptive immune responses, induce T-reg differentiation, promote angiogenesis, and even differentiate themselves into functional osteoclasts, promoting tumor growth [ 28 ]. MDSCs can be further divided into CD14+ monocytic (M-MDSC) and CD15+ granulocytic (G-MDSC) subsets being G-MDSC increased in the PB of MM patients [ 214 ]. Murine models show that MDSCs accumulate in the BM during MM progression in the early stages of the disease while circulating myeloid cells increase at later stages, and MDSC targeting reduces tumor load [ 215 ]. Moreover, the frequency of M-MDSCs in PB predicts outcomes after lenalidomide-dexamethasone treatment, where failure to achieve a response associates with an increase in M-MDSC frequency after treatment [ 216 ].

MDSCs perform an important suppressive activity of CD8 T cells and NKT cells in the BM. To achieve these suppressive functions, MDSCs produce arginases (ARG1), reactive oxygen species (ROS), cyclooxygenase-2 (COX2), inducible NOS (iNOS), IL6, IL10, IL18, and reduce metabolic factors required for T-cell activation. Moreover, MM cells induce MDSCs development from PB mononuclear cells in healthy donors, suggesting the relevance of bi-directional cell–cell communication [ 146 ]. In addition, soluble factors from MM cells, such as IL10, CCL5, MIP-1 or large amounts of IL6 generate MDSCs with T cell suppressive ability through Mcl-1 upregulation that enhances MDSCs survival [ 215 ]. In addition, BM stromal cells-derived exosomes in MM induced survival of MDSCs through STAT3 and STAT1 pathways and increased anti-apoptotic proteins Bcl-xL and Mcl-1 [ 217 ].

The relevance of MDSCs has been translated to patients. Thus, dual targeting of MM cells and MDSCs with biotherapeutic agents, such as Daratumumab [ 147 ], has emerged as a promising new therapeutic option with high potential, as recently reviewed by Uckun [ 218 ]. On the other hand, the α-chain of the IL3 receptor, known as CD123, is highly expressed on MDSCs [ 219 ]. For that reason, several biotherapeutic agents targeting CD123 have been developed, including the CD123-directed recombinant human IL3 fusion toxin Tagraxofusb (SL-401). SL-401 has been assessed in combination with the standard of care ( NCT02661022 ) in relapsed/refractory MM patients with promising early evidence of clinical activity. Altogether, these studies suggest that therapies targeting MDSCs might overcome the immunosuppressive environment in the BM of MM and increase the anti-tumor effect of additional treatments for MM patients.

4. Conclusions

To conclude, tumor cells in MM develop a smart network in the BM with non-hematological and hematological cells that create an environment that nurtures and protects them from traditional chemotherapy and novel based-immunotherapy treatments. Interactions with cells that do not belong to the hematological BM compartment form a feedback loop that leads to bone destruction, angiogenesis, and tumor expansion in the BM. Moreover, whereas immune cells are supposed to perform tumor surveillance, MM cells and non-hematological cells in the BM can polarize the phenotype and activity of immune cells leading to immune evasion. Unraveling these interactions has allowed the development of novel treatments for MM patients. In addition, MM patients represent an elderly population with immunosenescent T cells, which might explain the lack of efficacy of some immunotherapy treatments.

Finally, finding the most appropriate treatment for each MM patient among all the available treatments is an urgent need that requires first to have a global picture of the proportion of the different cell subsets in the TME. Deciphering the cellular imbalance in the TME will help select the best treatment combination that could restore this imbalance for each patient. Indeed, novel technologies based on multi-immunofluorescence allow deciphering cell–cell interactions in the TME and the phenotype of cells that will help treat patients.

Acknowledgments

Figures were made with Biorender.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author Contributions

Both authors conceived the study. Both authors wrote and reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Etxebeste-Mitxeltorena M. Del Rincón-Loza I. Martín-Antonio B. Tumor Secretome to Adoptive Cellular Immunotherapy: Reduce Me Before I Make You My Partner Front. Immunol. 2021 12 717850 10.3389/fimmu.2021.717850 34447383 PMC8382692

2. Li W. Ng J.M.-K. Wong C.C. Ng E.K.W. Yu J. Molecular Alterations of Cancer Cell and Tumour Microenvironment in Metastatic Gastric Cancer Oncogene 2018 37 4903 4920 10.1038/s41388-018-0341-x 29795331 PMC6127089

3. Wu S.-M. Lin W.-Y. Shen C.-C. Pan H.-C. Keh-Bin W. Chen Y.-C. Jan Y.-J. Lai D.-W. Tang S.-C. Tien H.-R. Melatonin Set out to ER Stress Signaling Thwarts Epithelial Mesenchymal Transition and Peritoneal Dissemination via Calpain-Mediated C/EBPβ and NFκB Cleavage J. Pineal Res. 2016 60 142 154 10.1111/jpi.12295 26514342

4. Huang J. Xiao D. Li G. Ma J. Chen P. Yuan W. Hou F. Ge J. Zhong M. Tang Y. EphA2 Promotes Epithelial-Mesenchymal Transition through the Wnt/β-Catenin Pathway in Gastric Cancer Cells Oncogene 2014 33 2737 2747 10.1038/onc.2013.238 23752181

5. Baghban R. Roshangar L. Jahanban-Esfahlan R. Seidi K. Ebrahimi-Kalan A. Jaymand M. Kolahian S. Javaheri T. Zare P. Tumor Microenvironment Complexity and Therapeutic Implications at a Glance Cell Commun. Signal. 2020 18 59 10.1186/s12964-020-0530-4 32264958 PMC7140346

6. Oliver A.J. Lau P.K.H. Unsworth A.S. Loi S. Darcy P.K. Kershaw M.H. Slaney C.Y. Tissue-Dependent Tumor Microenvironments and Their Impact on Immunotherapy Responses Front. Immunol. 2018 9 70 10.3389/fimmu.2018.00070 29445373 PMC5797771

7. Hirata E. Sahai E. Tumor Microenvironment and Differential Responses to Therapy Cold Spring Harb. Perspect Med. 2017 7 a026781 10.1101/cshperspect.a026781 28213438 PMC5495051

8. Balkwill F.R. Capasso M. Hagemann T. The Tumor Microenvironment at a Glance J. Cell Sci. 2012 125 5591 5596 10.1242/jcs.116392 23420197

9. Bagchi S. Yuan R. Engleman E.G. Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance Annu. Rev. Pathol. 2021 16 223 249 10.1146/annurev-pathol-042020-042741 33197221

10. Tavora B. Reynolds L.E. Batista S. Demircioglu F. Fernandez I. Lechertier T. Lees D.M. Wong P.-P. Alexopoulou A. Elia G. Endothelial-Cell FAK Targeting Sensitizes Tumours to DNA-Damaging Therapy Nature 2014 514 112 116 10.1038/nature13541 25079333 PMC4533916

11. Battram A.M. Bachiller M. Martín-Antonio B. Senescence in the Development and Response to Cancer with Immunotherapy: A Double-Edged Sword Int. J. Mol. Sci. 2020 21 4346 10.3390/ijms21124346 PMC7352478 32570952

12. Bent E.H. Gilbert L.A. Hemann M.T. A Senescence Secretory Switch Mediated by PI3K/AKT/MTOR Activation Controls Chemoprotective Endothelial Secretory Responses Genes Dev. 2016 30 1811 1821 10.1101/gad.284851.116 27566778 PMC5024680

13. Jeong S.K. Kim J.S. Lee C.G. Park Y.-S. Kim S.D. Yoon S.O. Han D.H. Lee K.Y. Jeong M.H. Jo W.S. Tumor Associated Macrophages Provide the Survival Resistance of Tumor Cells to Hypoxic Microenvironmental Condition through IL-6 Receptor-Mediated Signals Immunobiology 2017 222 55 65 10.1016/j.imbio.2015.11.010 26705936

14. Shree T. Olson O.C. Elie B.T. Kester J.C. Garfall A.L. Simpson K. Bell-McGuinn K.M. Zabor E.C. Brogi E. Joyce J.A. Macrophages and Cathepsin Proteases Blunt Chemotherapeutic Response in Breast Cancer Genes Dev. 2011 25 2465 2479 10.1101/gad.180331.111 22156207 PMC3243057

15. Dijkgraaf E.M. Heusinkveld M. Tummers B. Vogelpoel L.T.C. Goedemans R. Jha V. Nortier J.W.R. Welters M.J.P. Kroep J.R. van der Burg S.H. Chemotherapy Alters Monocyte Differentiation to Favor Generation of Cancer-Supporting M2 Macrophages in the Tumor Microenvironment Cancer Res. 2013 73 2480 2492 10.1158/0008-5472.CAN-12-3542 23436796

16. Wang Z. Tang Y. Tan Y. Wei Q. Yu W. Cancer-Associated Fibroblasts in Radiotherapy: Challenges and New Opportunities Cell Commun. Signal 2019 17 47 10.1186/s12964-019-0362-2 31101063 PMC6525365

17. Tommelein J. De Vlieghere E. Verset L. Melsens E. Leenders J. Descamps B. Debucquoy A. Vanhove C. Pauwels P. Gespach C.P. Radiotherapy-Activated Cancer-Associated Fibroblasts Promote Tumor Progression through Paracrine IGF1R Activation Cancer Res. 2018 78 659 670 10.1158/0008-5472.CAN-17-0524 29217764

18. Wen S. Hou Y. Fu L. Xi L. Yang D. Zhao M. Qin Y. Sun K. Teng Y. Liu M. Cancer-Associated Fibroblast (CAF)-Derived IL32 Promotes Breast Cancer Cell Invasion and Metastasis via Integrin Β3-P38 MAPK Signalling Cancer Lett. 2019 442 320 332 10.1016/j.canlet.2018.10.015 30391782

19. Özdemir B.C. Pentcheva-Hoang T. Carstens J.L. Zheng X. Wu C.-C. Simpson T.R. Laklai H. Sugimoto H. Kahlert C. Novitskiy S.V. Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival Cancer Cell 2014 25 719 734 10.1016/j.ccr.2014.04.005 24856586 PMC4180632

20. Bui J.D. Schreiber R.D. Cancer Immunosurveillance, Immunoediting and Inflammation: Independent or Interdependent Processes? Curr. Opin. Immunol. 2007 19 203 208 10.1016/j.coi.2007.02.001 17292599

21. Gupta A. Probst H.C. Vuong V. Landshammer A. Muth S. Yagita H. Schwendener R. Pruschy M. Knuth A. van den Broek M. Radiotherapy Promotes Tumor-Specific Effector CD8+ T Cells via Dendritic Cell Activation J. Immunol. 2012 189 558 566 10.4049/jimmunol.1200563 22685313

22. Maude S.L. Laetsch T.W. Buechner J. Rives S. Boyer M. Bittencourt H. Bader P. Verneris M.R. Stefanski H.E. Myers G.D. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia N. Engl. J. Med. 2018 378 439 448 10.1056/NEJMoa1709866 29385370 PMC5996391

23. Ortíz-Maldonado V. Rives S. Castellà M. Alonso-Saladrigues A. Benítez-Ribas D. Caballero-Baños M. Baumann T. Cid J. Garcia-Rey E. Llanos C. CART19-BE-01: A Multicenter Trial of ARI-0001 Cell Therapy in Patients with CD19+ Relapsed/Refractory Malignancies Mol. Ther. 2021 29 636 644 10.1016/j.ymthe.2020.09.027 33010231 PMC7854276

24. Perez-Amill L. Suñe G. Antoñana-Vildosola A. Castella M. Najjar A. Bonet J. Fernández-Fuentes N. Inogés S. López A. Bueno C. Preclinical Development of a Humanized Chimeric Antigen Receptor against B Cell Maturation Antigen for Multiple Myeloma Haematologica 2021 106 173 184 10.3324/haematol.2019.228577 31919085 PMC7776337

25. Castella M. Fernández de Larrea C. Martín-Antonio B. Immunotherapy: A Novel Era of Promising Treatments for Multiple Myeloma Int. J. Mol. Sci. 2018 19 3613 10.3390/ijms19113613 PMC6274949 30445802

26. Martinez M. Moon E.K. CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment Front. Immunol. 2019 10 128 10.3389/fimmu.2019.00128 30804938 PMC6370640

27. Raje N. Berdeja J. Lin Y. Siegel D. Jagannath S. Madduri D. Liedtke M. Rosenblatt J. Maus M.V. Turka A. Anti-BCMA CAR T-Cell Therapy Bb2121 in Relapsed or Refractory Multiple Myeloma N. Engl. J. Med. 2019 380 1726 1737 10.1056/NEJMoa1817226 31042825 PMC8202968

28. García-Ortiz A. Rodríguez-García Y. Encinas J. Maroto-Martín E. Castellano E. Teixidó J. Martínez-López J. The Role of Tumor Microenvironment in Multiple Myeloma Development and Progression Cancers 2021 13 217 10.3390/cancers13020217 PMC7827690 33435306

29. Kumar S.K. Rajkumar V. Kyle R.A. van Duin M. Sonneveld P. Mateos M.-V. Gay F. Anderson K.C. Multiple Myeloma Nat. Rev. Dis. Primers. 2017 3 17046 10.1038/nrdp.2017.46 28726797

30. Bone Marrow Niches in Haematological Malignancies | Nature Reviews Cancer Available online: https://www.nature.com/articles/s41568-020-0245-2 (accessed on 20 June 2022) 10.1038/s41568-020-0245-2 PMC9912977 32112045

31. Glavey S.V. Naba A. Manier S. Clauser K. Tahri S. Park J. Reagan M.R. Moschetta M. Mishima Y. Gambella M. Proteomic Characterization of Human Multiple Myeloma Bone Marrow Extracellular Matrix Leukemia 2017 31 2426 2434 10.1038/leu.2017.102 28344315

32. Landowski T.H. Olashaw N.E. Agrawal D. Dalton W.S. Cell Adhesion-Mediated Drug Resistance (CAM-DR) Is Associated with Activation of NF-ΚB (RelB/P50) in Myeloma Cells Oncogene 2003 22 2417 2421 10.1038/sj.onc.1206315 12717418

33. Targeting the Bone Marrow Microenvironment in Multiple Myeloma-Kawano-2015-Immunological Review-Wiley Online Library Available online: https://onlinelibrary.wiley.com/doi/10.1111/imr.12233 (accessed on 23 May 2022) 10.1111/imr.12233 25510276

34. Kouroukis T.C. Baldassarre F.G. Haynes A.E. Imrie K. Reece D.E. Cheung M.C. Bortezomib in Multiple Myeloma: Systematic Review and Clinical Considerations Curr. Oncol. 2014 21 573 603 10.3747/co.21.1798 PMC4117625 25089109

35. Ghobrial I.M. Liu C.-J. Zavidij O. Azab A.K. Baz R. Laubach J.P. Mishima Y. Armand P. Munshi N.C. Basile F. Phase I/II Trial of the CXCR4 Inhibitor Plerixafor in Combination with Bortezomib as a Chemosensitization Strategy in Relapsed/Refractory Multiple Myeloma Am. J. Hematol. 2019 94 1244 1253 10.1002/ajh.25627 31456261

36. Ghobrial I.M. Myeloma as a Model for the Process of Metastasis: Implications for Therapy Blood 2012 120 20 30 10.1182/blood-2012-01-379024 22535658 PMC3390959

37. Méndez-Ferrer S. Michurina T.V. Ferraro F. Mazloom A.R. MacArthur B.D. Lira S.A. Scadden D.T. Ma’ayan A. Enikolopov G.N. Frenette P.S. Mesenchymal and Haematopoietic Stem Cells Form a Unique Bone Marrow Niche Nature 2010 466 829 834 10.1038/nature09262 20703299 PMC3146551

38. Dazzi F. Ramasamy R. Glennie S. Jones S.P. Roberts I. The Role of Mesenchymal Stem Cells in Haemopoiesis Blood Rev. 2006 20 161 171 10.1016/j.blre.2005.11.002 16364518

39. Hideshima T. Mitsiades C. Tonon G. Richardson P.G. Anderson K.C. Understanding Multiple Myeloma Pathogenesis in the Bone Marrow to Identify New Therapeutic Targets Nat. Rev. Cancer 2007 7 585 598 10.1038/nrc2189 17646864

40. Asosingh K. Vankerkhove V. Riet I.V. Camp B.V. Vanderkerken K. Selective in Vivo Growth of Lymphocyte Function- Associated Antigen-1–Positive Murine Myeloma Cells: Involvement of Function-Associated Antigen-1–Mediated Homotypic Cell-Cell Adhesion Exp. Hematol. 2003 31 48 55 10.1016/S0301-472X(02)00970-0 12543106

41. Schmidmaier R. Mandl-Weber S. Gaul L. Baumann P. Bumeder I. Straka C. Emmerich B. Inhibition of Lymphocyte Function Associated Antigen 1 by LFA878 Induces Apoptosis in Multiple Myeloma Cells and Is Associated with Downregulation of the Focal Adhesion Kinase/Phosphatidylinositol 3 Kinase/Akt Pathway Int. J. Oncol. 2007 31 969 976 10.3892/ijo.31.4.969 17786331

42. Harmer D. Falank C. Reagan M.R. Interleukin-6 Interweaves the Bone Marrow Microenvironment, Bone Loss, and Multiple Myeloma Front. Endocrinol. 2019 9 788 10.3389/fendo.2018.00788 PMC6333051 30671025

43. Hideshima T. Bergsagel P.L. Kuehl W.M. Anderson K.C. Advances in Biology of Multiple Myeloma: Clinical Applications Blood 2004 104 607 618 10.1182/blood-2004-01-0037 15090448

44. Orlowski R.Z. Gercheva L. Williams C. Sutherland H. Robak T. Masszi T. Goranova-Marinova V. Dimopoulos M.A. Cavenagh J.D. Špička I. A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Siltuximab (Anti-IL-6 MAb) and Bortezomib versus Bortezomib Alone in Patients with Relapsed or Refractory Multiple Myeloma Am. J. Hematol. 2015 90 42 49 10.1002/ajh.23868 25294016 PMC4737504

45. Matsuyama Y. Nagashima T. Honne K. Kamata Y. Iwamoto M. Okazaki H. Sato K. Ozawa K. Minota S. Successful Treatment of a Patient with Rheumatoid Arthritis and IgA-κ Multiple Myeloma with Tocilizumab Intern. Med. 2011 50 639 642 10.2169/internalmedicine.50.4636 21422694

46. Corre J. Mahtouk K. Attal M. Gadelorge M. Huynh A. Fleury-Cappellesso S. Danho C. Laharrague P. Klein B. Rème T. Bone Marrow Mesenchymal Stem Cells Are Abnormal in Multiple Myeloma Leukemia 2007 21 1079 1088 10.1038/sj.leu.2404621 17344918 PMC2346535

47. Zdzisińska B. Bojarska-Junak A. Dmoszyńska A. Kandefer-Szerszeń M. Abnormal Cytokine Production by Bone Marrow Stromal Cells of Multiple Myeloma Patients in Response to RPMI8226 Myeloma Cells Arch. Immunol. Ther. Exp. 2008 56 207 10.1007/s00005-008-0022-5 18512025 PMC2766495

48. Deng M. Yuan H. Peng H. Liu S. Xiao X. Wang Z. Zhang G. Xiao H. Mesenchymal Stem Cells Inhibit the Effects of Dexamethasone in Multiple Myeloma Cells Stem Cells Int. 2022 2022 e4855517 10.1155/2022/4855517 35419059 PMC9001108

49. BAFF and APRIL Protect Myeloma Cells from Apoptosis Induced by Interleukin 6 Deprivation and Dexamethasone | Blood | American Society of Hematology Available online: https://ashpublications.org/blood/article/103/8/3148/18054/BAFF-and-APRIL-protect-myeloma-cells-from (accessed on 23 May 2022) 10.1182/blood-2003-06-1984 PMC2387243 15070697

50. Expression of BCMA, TACI, and BAFF-R in Multiple Myeloma: A Mechanism for Growth and Survival | Blood | American Society of Hematology Available online: https://ashpublications.org/blood/article/103/2/689/17829/Expression-of-BCMA-TACI-and-BAFF-R-in-multiple (accessed on 23 May 2022) 10.1182/blood-2003-06-2043 14512299

51. APRIL and BCMA Promote Human Multiple Myeloma Growth and Immunosuppression in the Bone Marrow Microenvironment | Blood | American Society of Hematology Available online: https://ashpublications.org/blood/article/127/25/3225/35206/APRIL-and-BCMA-promote-human-multiple-myeloma (accessed on 23 May 2022) 10.1182/blood-2016-01-691162 PMC4920023 27127303

52. Lee L. Draper B. Chaplin N. Philip B. Chin M. Galas-Filipowicz D. Onuoha S. Thomas S. Baldan V. Bughda R. An APRIL-Based Chimeric Antigen Receptor for Dual Targeting of BCMA and TACI in Multiple Myeloma Blood 2018 131 746 758 10.1182/blood-2017-05-781351 29284597 PMC5922275

53. Holthof L.C. van der Schans J.J. Katsarou A. Poels R. Gelderloos A.T. Drent E. van Hal-van Veen S.E. Li F. Zweegman S. van de Donk N.W.C.J. Bone Marrow Mesenchymal Stromal Cells Can Render Multiple Myeloma Cells Resistant to Cytotoxic Machinery of CAR T Cells through Inhibition of Apoptosis Clin. Cancer Res. 2021 27 3793 3803 10.1158/1078-0432.CCR-20-2188 33883175

54. The Role of Tumor Necrosis Factor α in the Pathophysiology of Human Multiple Myeloma: Therapeutic Applications | Oncogene Available online: https://www.nature.com/articles/1204623 (accessed on 23 May 2022) 10.1038/sj.onc.1204623 11494147

55. Tsubaki M. Komai M. Itoh T. Imano M. Sakamoto K. Shimaoka H. Ogawa N. Mashimo K. Fujiwara D. Takeda T. Inhibition of the Tumour Necrosis Factor-Alpha Autocrine Loop Enhances the Sensitivity of Multiple Myeloma Cells to Anticancer Drugs Eur. J. Cancer 2013 49 3708 3717 10.1016/j.ejca.2013.07.010 23932230

56. Calip G.S. Lee W.-J. Lee T.A. Schumock G.T. Chiu B.C.-H. Tumor Necrosis Factor-Alpha Inhibitor Medications for Inflammatory Conditions and Incidence of Multiple Myeloma Blood 2015 126 2954 10.1182/blood.V126.23.2954.2954

57. Sebba A. Tocilizumab: The First Interleukin-6-Receptor Inhibitor Am. J. Health Syst. Pharm. 2008 65 1413 1418 10.2146/ajhp070449 18653811

58. Iyer S.P. Beck J.T. Stewart A.K. Shah J. Kelly K.R. Isaacs R. Bilic S. Sen S. Munshi N.C. A Phase IB Multicentre Dose-Determination Study of BHQ880 in Combination with Anti-Myeloma Therapy and Zoledronic Acid in Patients with Relapsed or Refractory Multiple Myeloma and Prior Skeletal-Related Events Br. J. Haematol. 2014 167 366 375 10.1111/bjh.13056 25139740

59. Raje N.S. Moreau P. Terpos E. Benboubker L. Grząśko N. Holstein S.A. Oriol A. Huang S.-Y. Beksac M. Kuliczkowski K. Phase 2 Study of Tabalumab, a Human Anti-B-Cell Activating Factor Antibody, with Bortezomib and Dexamethasone in Patients with Previously Treated Multiple Myeloma Br. J. Haematol. 2017 176 783 795 10.1111/bjh.14483 28005265

60. Roodman G.D. Osteoblast Function in Myeloma Bone 2011 48 135 140 10.1016/j.bone.2010.06.016 20601285

61. Gau Y.-C. Yeh T.-J. Hsu C.-M. Hsiao S.Y. Hsiao H.-H. Pathogenesis and Treatment of Myeloma-Related Bone Disease Int. J. Mol. Sci. 2022 23 3112 10.3390/ijms23063112 35328533 PMC8951013

62. Valentin-Opran A. Charhon S.A. Meunier P.J. Edouard C.M. Arlot M.E. Quantitative Histology of Myeloma-Induced Bone Changes Br. J. Haematol. 1982 52 601 610 10.1111/j.1365-2141.1982.tb03936.x 7138789

63. Choi S.J. Oba Y. Gazitt Y. Alsina M. Cruz J. Anderson J. Roodman G.D. Antisense Inhibition of Macrophage Inflammatory Protein 1-α Blocks Bone Destruction in a Model of Myeloma Bone Disease J. Clin. Investig. 2001 108 1833 1841 10.1172/JCI200113116 11748267 PMC209465

64. Abe M. Hiura K. Wilde J. Moriyama K. Hashimoto T. Ozaki S. Wakatsuki S. Kosaka M. Kido S. Inoue D. Role for Macrophage Inflammatory Protein (MIP)-1alpha and MIP-1beta in the Development of Osteolytic Lesions in Multiple Myeloma Blood 2002 100 2195 2202 10.1182/blood.V100.6.2195 12200385

65. Macrophage Inflammatory Protein-1α Is an Osteoclastogenic Factor in Myeloma That Is Independent of Receptor Activator of Nuclear Factor ΚB Ligand | Blood | American Society of Hematology Available online: https://ashpublications.org/blood/article/97/11/3349/107426/Macrophage-inflammatory-protein-1-is-an (accessed on 23 May 2022)

66. Notch-Directed Microenvironment Reprogramming in Myeloma: A Single Path to Multiple Outcomes | Leukemia Available online: https://www.nature.com/articles/leu20136 (accessed on 23 May 2022) 10.1038/leu.2013.6 23307030

67. Boyce B.F. Xing L. Functions of RANKL/RANK/OPG in Bone Modeling and Remodeling Arch. Biochem. Biophys. 2008 473 139 146 10.1016/j.abb.2008.03.018 18395508 PMC2413418

68. Michigami T. Shimizu N. Williams P.J. Niewolna M. Dallas S.L. Mundy G.R. Yoneda T. Cell-Cell Contact between Marrow Stromal Cells and Myeloma Cells via VCAM-1 and Alpha (4) Beta (1)-Integrin Enhances Production of Osteoclast-Stimulating Activity Blood 2000 96 1953 1960 10.1182/blood.V96.5.1953 10961900

69. Terpos E. Raje N. Croucher P. Garcia-Sanz R. Leleu X. Pasteiner W. Wang Y. Glennane A. Canon J. Pawlyn C. Denosumab Compared with Zoledronic Acid on PFS in Multiple Myeloma: Exploratory Results of an International Phase 3 Study Blood Adv. 2021 5 725 736 10.1182/bloodadvances.2020002378 33560384 PMC7876889

70. Huang S.-Y. Yoon S.-S. Shimizu K. Chng W.J. Chang C.-S. Wong R.S.-M. Gao S. Wang Y. Gordon S.W. Glennane A. Denosumab Versus Zoledronic Acid in Bone Disease Treatment of Newly Diagnosed Multiple Myeloma: An International, Double-Blind, Randomized Controlled Phase 3 Study—Asian Subgroup Analysis Adv. Ther. 2020 37 3404 3416 10.1007/s12325-020-01395-x 32524500 PMC7467415

71. Hanley D.A. Adachi J.D. Bell A. Brown V. Denosumab: Mechanism of Action and Clinical Outcomes Int. J. Clin. Pract. 2012 66 1139 1146 10.1111/ijcp.12022 22967310 PMC3549483

72. Myeloma Cells Block RUNX2/CBFA1 Activity in Human Bone Marrow Osteoblast Progenitors and Inhibit Osteoblast Formation and Differentiation | Blood | American Society of Hematology Available online: https://ashpublications.org/blood/article/106/7/2472/21687/Myeloma-cells-block-RUNX2-CBFA1-activity-in-human (accessed on 23 May 2022)

73. Osteoprotegerin Is Bound, Internalized, and Degraded by Multiple Myeloma Cells | Blood | American Society of Hematology Available online: https://ashpublications.org/blood/article/100/8/3002/106454/Osteoprotegerin-is-bound-internalized-and-degraded (accessed on 23 May 2022) 10.1182/blood-2002-04-1190 12351414

74. Mori Y. Shimizu N. Dallas M. Niewolna M. Story B. Williams P.J. Mundy G.R. Yoneda T. Anti-A4 Integrin Antibody Suppresses the Development of Multiple Myeloma and Associated Osteoclastic Osteolysis Blood 2004 104 2149 2154 10.1182/blood-2004-01-0236 15138161

75. Padmanabhan S. Beck J.T. Kelly K.R. Munshi N.C. Dzik-Jurasz A. Gangolli E. Ettenberg S. Miner K. Bilic S. Whyte W. A Phase I/II Study of BHQ880, a Novel Osteoblat Activating, Anti-DKK1 Human Monoclonal Antibody, in Relapsed and Refractory Multiple Myeloma (MM) Patients Treated with Zoledronic Acid (Zol) and Anti-Myeloma Therapy (MM Tx) Blood 2009 114 750 10.1182/blood.V114.22.750.750

76. Vacca A. Ria R. Reale A. Ribatti D. Angiogenesis in Multiple Myeloma Angiogenes. Lymphangiogenes. Clin. Implic. 2014 99 180 196 10.1159/000353312 24217610

77. Ribatti D. Nico B. Vacca A. Multiple Myeloma as a Model for the Role of Bone Marrow Niches in the Control of Angiogenesis Int. Rev. Cell Mol. Biol. 2015 314 259 282 10.1016/bs.ircmb.2014.10.004 25619720

78. Mondello P. Cuzzocrea S. Navarra M. Mian M. Bone Marrow Micro-Environment Is a Crucial Player for Myelomagenesis and Disease Progression Oncotarget 2017 8 20394 20409 10.18632/oncotarget.14610 28099912 PMC5386771

79. Hanahan D. Weinberg R.A. Hallmarks of Cancer: The next Generation Cell 2011 144 646 674 10.1016/j.cell.2011.02.013 21376230

80. Rajkumar S.V. Mesa R.A. Fonseca R. Schroeder G. Plevak M.F. Dispenzieri A. Lacy M.Q. Lust J.A. Witzig T.E. Gertz M.A. Bone Marrow Angiogenesis in 400 Patients with Monoclonal Gammopathy of Undetermined Significance, Multiple Myeloma, and Primary Amyloidosis Clin. Cancer Res. 2002 8 2210 2216 12114422

81. Bhaskar A. Tiwary B.N. Hypoxia Inducible Factor-1 Alpha and Multiple Myeloma Int. J. Adv. Res. 2016 4 706 715 PMC4760640 26900575

82. Angiogenic Switch during 5T2MM Murine Myeloma Tumorigenesis: Role of CD45 Heterogeneity | Blood | American Society of Hematology Available online: https://ashpublications.org/blood/article/103/8/3131/18020/Angiogenic-switch-during-5T2MM-murine-myeloma (accessed on 24 May 2022) 10.1182/blood-2003-08-2946 15070695

83. Ria R. Todoerti K. Berardi S. Coluccia A.M.L. De Luisi A. Mattioli M. Ronchetti D. Morabito F. Guarini A. Petrucci M.T. Gene Expression Profiling of Bone Marrow Endothelial Cells in Patients with Multiple Myeloma Clin. Cancer Res. 2009 15 5369 5378 10.1158/1078-0432.CCR-09-0040 19690192

84. Solimando A.G. Summa S.D. Vacca A. Ribatti D. Cancer-Associated Angiogenesis: The Endothelial Cell as a Checkpoint for Immunological Patrolling Cancers 2020 12 3380 10.3390/cancers12113380 33203154 PMC7696032

85. Ribatti D. Vacca A. Nico B. Roncali L. Dammacco F. Postnatal Vasculogenesis Mech. Dev. 2001 100 157 163 10.1016/S0925-4773(00)00522-0 11165474

86. Moschetta M. Mishima Y. Kawano Y. Manier S. Paiva B. Palomera L. Aljawai Y. Calcinotto A. Unitt C. Sahin I. Targeting Vasculogenesis to Prevent Progression in Multiple Myeloma Leukemia 2016 30 1103 1115 10.1038/leu.2016.3 26859080

87. Tenreiro M.M. Correia M.L. Brito M.A. Endothelial Progenitor Cells in Multiple Myeloma Neovascularization: A Brick to the Wall Angiogenesis 2017 20 443 462 10.1007/s10456-017-9571-8 28840415

88. Reale A. Melaccio A. Lamanuzzi A. Saltarella I. Dammacco F. Vacca A. Ria R. Functional and Biological Role of Endothelial Precursor Cells in Tumour Progression: A New Potential Therapeutic Target in Haematological Malignancies Stem. Cells Int. 2015 2016 e7954580 10.1155/2016/7954580 PMC4691637 26788072

89. Sweeney M. Foldes G. It Takes Two: Endothelial-Perivascular Cell Cross-Talk in Vascular Development and Disease Front. Cardiovasc. Med. 2018 5 154 10.3389/fcvm.2018.00154 30425990 PMC6218412

90. Dankbar B. Padró T. Leo R. Feldmann B. Kropff M. Mesters R.M. Serve H. Berdel W.E. Kienast J. Vascular Endothelial Growth Factor and Interleukin-6 in Paracrine Tumor-Stromal Cell Interactions in Multiple Myeloma Blood 2000 95 2630 2636 10.1182/blood.V95.8.2630 10753844

91. Ria R. Melaccio A. Racanelli V. Vacca A. Anti-VEGF Drugs in the Treatment of Multiple Myeloma Patients J. Clin. Med. 2020 9 1765 10.3390/jcm9061765 PMC7355441 32517267

92. Somlo G. Lashkari A. Bellamy W. Zimmerman T.M. Tuscano J.M. O’Donnell M.R. Mohrbacher A.F. Forman S.J. Frankel P. Chen H.X. Phase II Randomized Trial of Bevacizumab versus Bevacizumab and Thalidomide for Relapsed/Refractory Multiple Myeloma: A California Cancer Consortium Trial Br. J. Haematol. 2011 154 533 535 10.1111/j.1365-2141.2011.08623.x 21517811 PMC3272081

93. White D. Kassim A. Bhaskar B. Yi J. Wamstad K. Paton V.E. Results from AMBER, a Randomized Phase 2 Study of Bevacizumab and Bortezomib versus Bortezomib in Relapsed or Refractory Multiple Myeloma Cancer 2013 119 339 347 10.1002/cncr.27745 22811009

94. Yordanova A. Hose D. Neben K. Witzens-Harig M. Gütgemann I. Raab M.-S. Moehler T. Goldschmidt H. Schmidt-Wolf I.G. Sorafenib in Patients with Refractory or Recurrent Multiple Myeloma Hematol. Oncol. 2013 31 197 200 10.1002/hon.2043 23494836

95. Srkalovic G. Hussein M.A. Hoering A. Zonder J.A. Popplewell L.L. Trivedi H. Mazzoni S. Sexton R. Orlowski R.Z. Barlogie B. A Phase II Trial of BAY 43-9006 (Sorafenib) (NSC-724772) in Patients with Relapsing and Resistant Multiple Myeloma: SWOG S0434 Cancer Med. 2014 3 1275 1283 10.1002/cam4.276 24913924 PMC4302677

96. Kumar S. Witzig T.E. Dispenzieri A. Lacy M.Q. Wellik L.E. Fonseca R. Lust J.A. Gertz M.A. Kyle R.A. Greipp P.R. Effect of Thalidomide Therapy on Bone Marrow Angiogenesis in Multiple Myeloma Leukemia 2004 18 624 627 10.1038/sj.leu.2403285 14749707

97. Terpos E. Katodritou E. Symeonidis A. Zagouri F. Gerofotis A. Christopoulou G. Gavriatopoulou M. Christoulas D. Ntanasis-Stathopoulos I. Kourakli A. Effect of Induction Therapy with Lenalidomide, Doxorubicin and Dexamethasone on Bone Remodeling and Angiogenesis in Newly Diagnosed Multiple Myeloma Int. J. Cancer 2019 145 559 568 10.1002/ijc.32125 30650184

98. Deng M. Yuan H. Liu S. Hu Z. Xiao H. Exosome-Transmitted LINC00461 Promotes Multiple Myeloma Cell Proliferation and Suppresses Apoptosis by Modulating MicroRNA/BCL-2 Expression Cytotherapy 2019 21 96 106 10.1016/j.jcyt.2018.10.006 30409700

99. Scavelli C. Di Pietro G. Cirulli T. Coluccia M. Boccarelli A. Giannini T. Mangialardi G. Bertieri R. Coluccia A.M.L. Ribatti D. Zoledronic Acid Affects Over-Angiogenic Phenotype of Endothelial Cells in Patients with Multiple Myeloma Mol. Cancer Ther. 2007 6 3256 3262 10.1158/1535-7163.MCT-07-0311 18089719

100. Guillerey C. Harjunpää H. Carrié N. Kassem S. Teo T. Miles K. Krumeich S. Weulersse M. Cuisinier M. Stannard K. TIGIT Immune Checkpoint Blockade Restores CD8+ T-Cell Immunity against Multiple Myeloma Blood 2018 132 1689 1694 10.1182/blood-2018-01-825265 29986909

101. Noonan K.A. Huff C.A. Davis J. Lemas M.V. Fiorino S. Bitzan J. Ferguson A. Emerling A. Luznik L. Matsui W. Adoptive Transfer of Activated Marrow-Infiltrating Lymphocytes Induces Measurable Antitumor Immunity in the Bone Marrow in Multiple Myeloma Sci. Transl. Med. 2015 7 288ra78 10.1126/scitranslmed.aaa7014 PMC4634889 25995224

102. Teijeira A. Garasa S. Etxeberria I. Gato-Cañas M. Melero I. Delgoffe G.M. Metabolic Consequences of T-Cell Costimulation in Anticancer Immunity Cancer Immunol. Res. 2019 7 1564 1569 10.1158/2326-6066.CIR-19-0115 31575551

103. Wherry E.J. T Cell Exhaustion Nat. Immunol. 2011 12 492 499 10.1038/ni.2035 21739672

104. Arai Y. Choi U. Corsino C.I. Koontz S.M. Tajima M. Sweeney C.L. Black M.A. Feldman S.A. Dinauer M.C. Malech H.L. Enhanced Expression of CXCR4 Facilitates C-Kit-Targeted CAR-T Cell Trafficking to Bone Marrow and Enables Donor Stem Cell Engraftment Biol. Blood Marrow Transplant. 2018 24 S311 10.1016/j.bbmt.2017.12.359 PMC5993968 29622475

105. Alsina M. Shah N. Raje N.S. Jagannath S. Madduri D. Kaufman J.L. Berdeja J.G. Updated Results from the Phase I CRB-402 Study of Anti-Bcma CAR-T Cell Therapy Bb21217 in Patients with Relapsed and Refractory Multiple Myeloma: Correlation of Expansion and Duration of Response with T Cell Phenotypes Blood 2020 136 25 26 10.1182/blood-2020-140410

106. Le Calvez B. Moreau P. Touzeau C. Immune Checkpoint Inhibitors for the Treatment of Myeloma: Novel Investigational Options Expert Opin. Investig. Drugs 2021 30 965 973 10.1080/13543784.2021.1955103 34253136

107. Ogawara H. Handa H. Yamazaki T. Toda T. Yoshida K. Nishimoto N. Al-ma’Quol W.H.S. Kaneko Y. Matsushima T. Tsukamoto N. High Th1/Th2 Ratio in Patients with Multiple Myeloma Leuk. Res. 2005 29 135 140 10.1016/j.leukres.2004.06.003 15607360

108. Frassanito M.A. Cusmai A. Dammacco F. Deregulated Cytokine Network and Defective Th1 Immune Response in Multiple Myeloma Clin. Exp. Immunol. 2001 125 190 197 10.1046/j.1365-2249.2001.01582.x 11529908 PMC1906126

109. Verkleij C.P.M. Broekmans M.E.C. van Duin M. Frerichs K.A. Kuiper R. de Jonge A.V. Kaiser M. Morgan G. Axel A. Boominathan R. Preclinical Activity and Determinants of Response of the GPRC5DxCD3 Bispecific Antibody Talquetamab in Multiple Myeloma Blood Adv. 2021 5 2196 2215 10.1182/bloodadvances.2020003805 33890981 PMC8095149

110. Green D.J. Pont M. Sather B.D. Cowan A.J. Turtle C.J. Till B.G. Nagengast A.M. Libby E.N. III Becker P.S. Coffey D.G. Fully Human Bcma Targeted Chimeric Antigen Receptor T Cells Administered in a Defined Composition Demonstrate Potency at Low Doses in Advanced Stage High Risk Multiple Myeloma Blood 2018 132 1011 10.1182/blood-2018-99-117729

111. Garfall A.L. Dancy E.K. Cohen A.D. Hwang W.-T. Fraietta J.A. Davis M.M. Levine B.L. Siegel D.L. Stadtmauer E.A. Vogl D.T. T-Cell Phenotypes Associated with Effective CAR T-Cell Therapy in Postinduction vs Relapsed Multiple Myeloma Blood Adv. 2019 3 2812 2815 10.1182/bloodadvances.2019000600 31575532 PMC6784521

112. Giannopoulos K. Kaminska W. Hus I. Dmoszynska A. The Frequency of T Regulatory Cells Modulates the Survival of Multiple Myeloma Patients: Detailed Characterisation of Immune Status in Multiple Myeloma Br. J. Cancer 2012 106 546 552 10.1038/bjc.2011.575 22223085 PMC3273338

113. Alrasheed N. Lee L. Ghorani E. Henry J.Y. Conde L. Chin M. Galas-Filipowicz D. Furness A.J.S. Chavda S.J. Richards H. Marrow-Infiltrating Regulatory T Cells Correlate with the Presence of Dysfunctional CD4+PD-1+ Cells and Inferior Survival in Patients with Newly Diagnosed Multiple Myeloma Clin. Cancer Res. 2020 26 3443 3454 10.1158/1078-0432.CCR-19-1714 32220887

114. Feyler S. Scott G.B. Parrish C. Jarmin S. Evans P. Short M. McKinley K. Selby P.J. Cook G. Tumour Cell Generation of Inducible Regulatory T-Cells in Multiple Myeloma Is Contact-Dependent and Antigen-Presenting Cell-Independent PLoS ONE 2012 7 e35981 10.1371/journal.pone.0035981 22666318 PMC3362588

115. Takeuchi Y. Nishikawa H. Roles of Regulatory T Cells in Cancer Immunity Int. Immunol. 2016 28 401 409 10.1093/intimm/dxw025 27160722 PMC4986235

116. Braga W.M.T. da Silva B.R. de Carvalho A.C. Maekawa Y.H. Bortoluzzo A.B. Rizzatti E.G. Atanackovic D. Colleoni G.W.B. FOXP3 and CTLA4 Overexpression in Multiple Myeloma Bone Marrow as a Sign of Accumulation of CD4+ T Regulatory Cells Cancer Immunol. Immunother. 2014 63 1189 1197 10.1007/s00262-014-1589-9 25099367 PMC4209089

117. Dahlhoff J. Manz H. Steinfatt T. Delgado-Tascon J. Seebacher E. Schneider T. Wilnit A. Mokhtari Z. Tabares P. Böckle D. Transient Regulatory T-Cell Targeting Triggers Immune Control of Multiple Myeloma and Prevents Disease Progression Leukemia 2022 36 790 800 10.1038/s41375-021-01422-y 34584204 PMC8885410

118. Zhou L. Ivanov I.I. Spolski R. Min R. Shenderov K. Egawa T. Levy D.E. Leonard W.J. Littman D.R. IL-6 Programs TH-17 Cell Differentiation by Promoting Sequential Engagement of the IL-21 and IL-23 Pathways Nat. Immunol. 2007 8 967 974 10.1038/ni1488 17581537

119. Prabhala R.H. Pelluru D. Fulciniti M. Prabhala H.K. Nanjappa P. Song W. Pai C. Amin S. Tai Y.-T. Richardson P.G. Elevated IL-17 Produced by TH17 Cells Promotes Myeloma Cell Growth and Inhibits Immune Function in Multiple Myeloma Blood 2010 115 5385 5392 10.1182/blood-2009-10-246660 20395418 PMC2902136

120. Lei L. Sun J. Han J. Jiang X. Wang Z. Chen L. Interleukin-17 Induces Pyroptosis in Osteoblasts through the NLRP3 Inflammasome Pathway in Vitro Int. Immunopharmacol. 2021 96 107781 10.1016/j.intimp.2021.107781 34004438

121. Zhao L.-J. Gao S. Li X. Effects of Thalidomide on the Ratio of Th17 to Treg Cells in Peripheral Blood and Expression of IL-17 and IL-35 in Patients with Multiple Myeloma Zhongguo Shi Yan Xue Ye Xue Za Zhi 2018 26 187 191 10.7534/j.issn.1009-2137.2018.01.032 29397841

122. Prabhala R.H. Fulciniti M. Pelluru D. Rashid N. Nigroiu A. Nanjappa P. Pai C. Lee S. Prabhala N.S. Bandi R.L. Targeting IL-17A in Multiple Myeloma: A Potential Novel Therapeutic Approach in Myeloma Leukemia 2016 30 379 389 10.1038/leu.2015.228 26293646 PMC4740263

123. Suen H. Brown R. Yang S. Weatherburn C. Ho P.J. Woodland N. Nassif N. Barbaro P. Bryant C. Hart D. Multiple Myeloma Causes Clonal T-Cell Immunosenescence: Identification of Potential Novel Targets for Promoting Tumour Immunity and Implications for Checkpoint Blockade Leukemia 2016 30 1716 1724 10.1038/leu.2016.84 27102208

124. Das R.K. Vernau L. Grupp S.A. Barrett D.M. Naïve T-Cell Deficits at Diagnosis and after Chemotherapy Impair Cell Therapy Potential in Pediatric Cancers Cancer Discov. 2019 9 492 499 10.1158/2159-8290.CD-18-1314 30630850 PMC6676489

125. Arasanz H. Zuazo M. Bocanegra A. Gato M. Martínez-Aguillo M. Morilla I. Fernández G. Hernández B. López P. Alberdi N. Early Detection of Hyperprogressive Disease in Non-Small Cell Lung Cancer by Monitoring of Systemic T Cell Dynamics Cancers 2020 12 344 10.3390/cancers12020344 32033028 PMC7073153

126. Battram A.M. Bachiller M. Lopez V. Fernández de Larrea C. Urbano-Ispizua A. Martín-Antonio B. IL-15 Enhances the Persistence and Function of BCMA-Targeting CAR-T Cells Compared to IL-2 or IL-15/IL-7 by Limiting CAR-T Cell Dysfunction and Differentiation Cancers 2021 13 3534 10.3390/cancers13143534 34298748 PMC8304527

127. Lanna A. Gomes D.C.O. Muller-Durovic B. McDonnell T. Escors D. Gilroy D.W. Lee J.H. Karin M. Akbar A.N. A Sestrin-Dependent Erk-Jnk-P38 MAPK Activation Complex Inhibits Immunity during Aging Nat. Immunol. 2017 18 354 363 10.1038/ni.3665 28114291 PMC5321575

128. Jinushi M. Vanneman M. Munshi N.C. Tai Y.-T. Prabhala R.H. Ritz J. Neuberg D. Anderson K.C. Carrasco D.R. Dranoff G. MHC Class I Chain-Related Protein A Antibodies and Shedding Are Associated with the Progression of Multiple Myeloma Proc. Natl. Acad. Sci. USA 2008 105 1285 1290 10.1073/pnas.0711293105 18202175 PMC2234130

129. Benson D.M. Jr. Bakan C.E. Mishra A. Hofmeister C.C. Efebera Y. Becknell B. Baiocchi R.A. Zhang J. Yu J. Smith M.K. The PD-1/PD-L1 Axis Modulates the Natural Killer Cell versus Multiple Myeloma Effect: A Therapeutic Target for CT-011, a Novel Monoclonal Anti–PD-1 Antibody Blood 2010 116 2286 2294 10.1182/blood-2010-02-271874 20460501 PMC3490105

130. Pazina T. MacFarlane A.W. Bernabei L. Dulaimi E. Kotcher R. Yam C. Bezman N.A. Robbins M.D. Ross E.A. Campbell K.S. Alterations of NK Cell Phenotype in the Disease Course of Multiple Myeloma Cancers 2021 13 226 10.3390/cancers13020226 PMC7827733 33435153

131. Cifaldi L. Prencipe G. Caiello I. Bracaglia C. Locatelli F. De Benedetti F. Strippoli R. Inhibition of Natural Killer Cell Cytotoxicity by Interleukin-6: Implications for the Pathogenesis of Macrophage Activation Syndrome Arthritis Rheumatol. 2015 67 3037 3046 10.1002/art.39295 26251193

132. Tamura H. Ishibashi M. Yamashita T. Tanosaki S. Okuyama N. Kondo A. Hyodo H. Shinya E. Takahashi H. Dong H. Marrow Stromal Cells Induce B7-H1 Expression on Myeloma Cells, Generating Aggressive Characteristics in Multiple Myeloma Leukemia 2013 27 464 472 10.1038/leu.2012.213 22828443

133. Tamura H. Ishibashi M. Sunakawa-Kii M. Inokuchi K. PD-L1-PD-1 Pathway in the Pathophysiology of Multiple Myeloma Cancers 2020 12 924 10.3390/cancers12040924 PMC7226506 32290052

134. Elkabets M. Ribeiro V.S.G. Dinarello C.A. Ostrand-Rosenberg S. Di Santo J.P. Apte R.N. Vosshenrich C.A.J. IL-1β Regulates a Novel Myeloid-Derived Suppressor Cell Subset That Impairs NK Cell Development and Function Eur. J. Immunol. 2010 40 3347 3357 10.1002/eji.201041037 21110318 PMC3373225

135. Ponzetta A. Benigni G. Antonangeli F. Sciumè G. Sanseviero E. Zingoni A. Ricciardi M.R. Petrucci M.T. Santoni A. Bernardini G. Multiple Myeloma Impairs Bone Marrow Localization of Effector Natural Killer Cells by Altering the Chemokine Microenvironment Cancer Res. 2015 75 4766 4777 10.1158/0008-5472.CAN-15-1320 26438594

136. Clara J.A. Childs R.W. Harnessing Natural Killer Cells for the Treatment of Multiple Myeloma Semin. Oncol. 2022 49 69 85 10.1053/j.seminoncol.2022.01.004 35125241

137. Bachiller M. Battram A.M. Perez-Amill L. Martín-Antonio B. Natural Killer Cells in Immunotherapy: Are We Nearly There? Cancers 2020 12 3139 10.3390/cancers12113139 PMC7694052 33120910

138. Flores-Borja F. Bosma A. Ng D. Reddy V. Ehrenstein M.R. Isenberg D.A. Mauri C. CD19+CD24hiCD38hi B Cells Maintain Regulatory T Cells While Limiting TH1 and TH17 Differentiation Sci. Transl. Med. 2013 5 173ra23 10.1126/scitranslmed.3005407 23427243

139. Zhang L. Tai Y.-T. Ho M. Xing L. Chauhan D. Gang A. Qiu L. Anderson K.C. Regulatory B Cell-Myeloma Cell Interaction Confers Immunosuppression and Promotes Their Survival in the Bone Marrow Milieu Blood Cancer J. 2017 7 e547 10.1038/bcj.2017.24 28338671 PMC5380908

140. Beider K. Bitner H. Leiba M. Gutwein O. Koren-Michowitz M. Ostrovsky O. Abraham M. Wald H. Galun E. Peled A. Multiple Myeloma Cells Recruit Tumor-Supportive Macrophages through the CXCR4/CXCL12 Axis and Promote Their Polarization toward the M2 Phenotype Oncotarget 2014 5 11283 11296 10.18632/oncotarget.2207 25526031 PMC4294328

141. Andersen M.N. Andersen N.F. Rødgaard-Hansen S. Hokland M. Abildgaard N. Møller H.J. The Novel Biomarker of Alternative Macrophage Activation, Soluble Mannose Receptor (SMR/SCD206): Implications in Multiple Myeloma Leuk. Res. 2015 39 971 975 10.1016/j.leukres.2015.06.003 26169445

142. Xu R. Li Y. Yan H. Zhang E. Huang X. Chen Q. Chen J. Qu J. Liu Y. He J. CCL2 Promotes Macrophages-Associated Chemoresistance via MCPIP1 Dual Catalytic Activities in Multiple Myeloma Cell Death Dis. 2019 10 781 10.1038/s41419-019-2012-4 31611552 PMC6791869

143. Russ A. Hua A.B. Montfort W.R. Rahman B. Riaz I.B. Khalid M.U. Carew J.S. Nawrocki S.T. Persky D. Anwer F. Blocking “Don’t Eat Me” Signal of CD47-SIRPα in Hematological Malignancies, an in-Depth Review Blood Rev. 2018 32 480 489 10.1016/j.blre.2018.04.005 29709247 PMC6186508

144. Opperman K.S. Vandyke K. Clark K.C. Coulter E.A. Hewett D.R. Mrozik K.M. Schwarz N. Evdokiou A. Croucher P.I. Psaltis P.J. Clodronate-Liposome Mediated Macrophage Depletion Abrogates Multiple Myeloma Tumor Establishment In Vivo Neoplasia 2019 21 777 787 10.1016/j.neo.2019.05.006 31247457 PMC6593350

145. Ries C.H. Cannarile M.A. Hoves S. Benz J. Wartha K. Runza V. Rey-Giraud F. Pradel L.P. Feuerhake F. Klaman I. Targeting Tumor-Associated Macrophages with Anti-CSF-1R Antibody Reveals a Strategy for Cancer Therapy Cancer Cell 2014 25 846 859 10.1016/j.ccr.2014.05.016 24898549

146. Görgün G.T. Whitehill G. Anderson J.L. Hideshima T. Maguire C. Laubach J. Raje N. Munshi N.C. Richardson P.G. Anderson K.C. Tumor-Promoting Immune-Suppressive Myeloid-Derived Suppressor Cells in the Multiple Myeloma Microenvironment in Humans Blood 2013 121 2975 2987 10.1182/blood-2012-08-448548 23321256 PMC3624943

147. Jakubowiak A.J. Kumar S. Medhekar R. Pei H. Lefebvre P. Kaila S. He J. Lafeuille M.-H. Cortoos A. Londhe A. Daratumumab Improves Depth of Response and Progression-Free Survival in Transplant-Ineligible, High-Risk, Newly Diagnosed Multiple Myeloma Oncologist 2022 27 e589 e596 10.1093/oncolo/oyac067 35462406 PMC9256027

148. Htut M. Gasparetto C. Zonder J. Martin T.G. III Scott E.C. Chen J. Shemesh S. Brooks C.L. Chauhan D. Anderson K.C. Results from Ongoing Phase 1/2 Trial of SL-401 in Combination with Pomalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma Blood 2016 128 5696 10.1182/blood.V128.22.5696.5696

149. Rossi M. Botta C. Correale P. Tassone P. Tagliaferri P. Immunologic Microenvironment and Personalized Treatment in Multiple Myeloma Expert Opin. Biol. Ther. 2013 13 (Suppl. S1) S83 S93 10.1517/14712598.2013.799130 23692463

150. Yamamoto L. Amodio N. Gulla A. Anderson K.C. Harnessing the Immune System Against Multiple Myeloma: Challenges and Opportunities Front. Oncol. 2021 10 606368 10.3389/fonc.2020.606368 33585226 PMC7873734

151. Moser-Katz T. Joseph N.S. Dhodapkar M.V. Lee K.P. Boise L.H. Game of Bones: How Myeloma Manipulates Its Microenvironment Front. Oncol. 2021 10 625199 10.3389/fonc.2020.625199 33634031 PMC7900622

152. Nakamura K. Smyth M.J. Martinet L. Cancer Immunoediting and Immune Dysregulation in Multiple Myeloma Blood 2020 136 2731 2740 10.1182/blood.2020006540 32645135

153. Whiteside T.L. The Tumor Microenvironment and Its Role in Promoting Tumor Growth Oncogene 2008 27 5904 5912 10.1038/onc.2008.271 18836471 PMC3689267

154. Kay N.E. Leong T.L. Bone N. Vesole D.H. Greipp P.R. Van Ness B. Oken M.M. Kyle R.A. Blood Levels of Immune Cells Predict Survival in Myeloma Patients: Results of an Eastern Cooperative Oncology Group Phase 3 Trial for Newly Diagnosed Multiple Myeloma Patients Blood 2001 98 23 28 10.1182/blood.V98.1.23 11418458

155. Raitakari M. Brown R.D. Gibson J. Joshua D.E. T Cells in Myeloma Hematol. Oncol. 2003 21 33 42 10.1002/hon.704 12605421

156. Wei F. Cheng X.-X. Xue J.Z. Xue S.-A. Emerging Strategies in TCR-Engineered T Cells Front. Immunol. 2022 13 850358 10.3389/fimmu.2022.850358 35432319 PMC9006933

157. Kasakovski D. Xu L. Li Y. T Cell Senescence and CAR-T Cell Exhaustion in Hematological Malignancies J. Hematol. Oncol. 2018 11 91 10.1186/s13045-018-0629-x 29973238 PMC6032767

158. Ab Rahman A.S. Strother R.M. Paddison J. New Zealand National Retrospective Cohort Study of Survival Outcomes of Patients with Metastatic Melanoma Receiving Immune-Checkpoint Inhibitors Asia Pac. J. Clin. Oncol. 2022 1 8 10.1111/ajco.13801 35686690

159. Das S. Johnson D.B. Immune-Related Adverse Events and Anti-Tumor Efficacy of Immune Checkpoint Inhibitors J. Immunother. Cancer 2019 7 306 10.1186/s40425-019-0805-8 31730012 PMC6858629

160. Yamazaki N. Uhara H. Fukushima S. Uchi H. Shibagaki N. Kiyohara Y. Tsutsumida A. Namikawa K. Okuyama R. Otsuka Y. Phase II Study of the Immune-Checkpoint Inhibitor Ipilimumab plus Dacarbazine in Japanese Patients with Previously Untreated, Unresectable or Metastatic Melanoma Cancer Chemother. Pharm. 2015 76 969 975 10.1007/s00280-015-2870-0 PMC4612320 26407818

161. Miller B.C. Sen D.R. Al Abosy R. Bi K. Virkud Y.V. LaFleur M.W. Yates K.B. Lako A. Felt K. Naik G.S. Subsets of Exhausted CD8+ T Cells Differentially Mediate Tumor Control and Respond to Checkpoint Blockade Nat. Immunol. 2019 20 326 336 10.1038/s41590-019-0312-6 30778252 PMC6673650

162. Zelle-Rieser C. Thangavadivel S. Biedermann R. Brunner A. Stoitzner P. Willenbacher E. Greil R. Jöhrer K. T Cells in Multiple Myeloma Display Features of Exhaustion and Senescence at the Tumor Site J. Hematol. Oncol. 2016 9 116 10.1186/s13045-016-0345-3 27809856 PMC5093947

163. Visram A. Kourelis T.V. Aging-Associated Immune System Changes in Multiple Myeloma: The Dark Side of the Moon Cancer Treat. Res. Commun. 2021 29 100494 10.1016/j.ctarc.2021.100494 34837796 PMC8744501

164. Frassanito M.A. Cusmai A. Iodice G. Dammacco F. Autocrine Interleukin-6 Production and Highly Malignant Multiple Myeloma: Relation with Resistance to Drug-Induced Apoptosis Blood 2001 97 483 489 10.1182/blood.V97.2.483 11154226

165. Fontenot J.D. Gavin M.A. Rudensky A.Y. Foxp3 Programs the Development and Function of CD4+CD25+ Regulatory T Cells Nat. Immunol. 2003 4 330 336 10.1038/ni904 12612578

166. Workman C.J. Szymczak-Workman A.L. Collison L.W. Pillai M.R. Vignali D.A.A. The Development and Function of Regulatory T Cells Cell Mol. Life Sci. 2009 66 2603 2622 10.1007/s00018-009-0026-2 19390784 PMC2715449

167. Curiel T.J. Regulatory T Cells and Treatment of Cancer Curr. Opin. Immunol. 2008 20 241 246 10.1016/j.coi.2008.04.008 18508251 PMC3319305

168. Hadjiaggelidou C. Katodritou E. Regulatory T-Cells and Multiple Myeloma: Implications in Tumor Immune Biology and Treatment J. Clin. Med. 2021 10 4588 10.3390/jcm10194588 34640606 PMC8509132

169. Raja K.R.M. Rihova L. Zahradova L. Klincova M. Penka M. Hajek R. Increased T Regulatory Cells Are Associated with Adverse Clinical Features and Predict Progression in Multiple Myeloma PLoS ONE 2012 7 e47077 10.1371/journal.pone.0047077 23071717 PMC3468567

170. Prabhala R.H. Neri P. Bae J.E. Tassone P. Shammas M.A. Allam C.K. Daley J.F. Chauhan D. Blanchard E. Thatte H.S. Dysfunctional T Regulatory Cells in Multiple Myeloma Blood 2006 107 301 304 10.1182/blood-2005-08-3101 16150935 PMC1895365

171. Noonan K. Marchionni L. Anderson J. Pardoll D. Roodman G.D. Borrello I. A Novel Role of IL-17–Producing Lymphocytes in Mediating Lytic Bone Disease in Multiple Myeloma Blood 2010 116 3554 3563 10.1182/blood-2010-05-283895 20664052 PMC4017298

172. Foglietta M. Castella B. Mariani S. Coscia M. Godio L. Ferracini R. Ruggeri M. Muccio V. Omedé P. Palumbo A. The Bone Marrow of Myeloma Patients Is Steadily Inhabited by a Normal-Sized Pool of Functional Regulatory T Cells Irrespectiveof the Disease Status Haematologica 2014 99 1605 1610 10.3324/haematol.2014.105866 24972771 PMC4181257

173. Sun L. Fu J. Zhou Y. Metabolism Controls the Balance of Th17/T-Regulatory Cells Front. Immunol. 2017 8 1632 10.3389/fimmu.2017.01632 29230216 PMC5712044

174. Rossi M. Altomare E. Botta C. Gallo Cantafio M.E. Sarvide S. Caracciolo D. Riillo C. Gaspari M. Taverna D. Conforti F. MiR-21 Antagonism Abrogates Th17 Tumor Promoting Functions in Multiple Myeloma Leukemia 2021 35 823 834 10.1038/s41375-020-0947-1 32632096

175. Ma T. Zhang Y. Zhou X. Xie P. Li J. A Unique Role of T Helper 17 Cells in Different Treatment Stages of Multiple Myeloma Clin. Lymphoma Myeloma Leuk. 2020 20 190 197 10.1016/j.clml.2019.12.009 31980418

176. Dhodapkar K.M. Barbuto S. Matthews P. Kukreja A. Mazumder A. Vesole D. Jagannath S. Dhodapkar M.V. Dendritic Cells Mediate the Induction of Polyfunctional Human IL17-Producing Cells (Th17-1 Cells) Enriched in the Bone Marrow of Patients with Myeloma Blood 2008 112 2878 2885 10.1182/blood-2008-03-143222 18669891 PMC2556623

177. Kale A. Sharma A. Stolzing A. Desprez P.-Y. Campisi J. Role of Immune Cells in the Removal of Deleterious Senescent Cells Immun. Ageing 2020 17 16 10.1186/s12979-020-00187-9 32518575 PMC7271494

178. Iannello A. Thompson T.W. Ardolino M. Lowe S.W. Raulet D.H. P53-Dependent Chemokine Production by Senescent Tumor Cells Supports NKG2D-Dependent Tumor Elimination by Natural Killer Cells J. Exp. Med. 2013 210 2057 2069 10.1084/jem.20130783 24043758 PMC3782044

179. Liu Q. Sun Z. Chen L. Memory T Cells: Strategies for Optimizing Tumor Immunotherapy Protein Cell 2020 11 549 564 10.1007/s13238-020-00707-9 32221812 PMC7381543

180. Thomas R. Wang W. Su D.-M. Contributions of Age-Related Thymic Involution to Immunosenescence and Inflammaging Immun. Ageing 2020 17 2 10.1186/s12979-020-0173-8 31988649 PMC6971920

181. Coder B.D. Wang H. Ruan L. Su D.-M. Thymic Involution Perturbs Negative Selection Leading to Autoreactive T Cells That Induce Chronic Inflammation J. Immunol. 2015 194 5825 5837 10.4049/jimmunol.1500082 25957168 PMC4458423

182. Rodrigues L.P. Teixeira V.R. Alencar-Silva T. Simonassi-Paiva B. Pereira R.W. Pogue R. Carvalho J.L. Hallmarks of Aging and Immunosenescence: Connecting the Dots Cytokine Growth Factor Rev. 2021 59 9 21 10.1016/j.cytogfr.2021.01.006 33551332

183. Rodriguez I.J. Lalinde Ruiz N. Llano León M. Martínez Enríquez L. del Montilla Velásquez M.P. Ortiz Aguirre J.P. Rodríguez Bohórquez O.M. Velandia Vargas E.A. Hernández E.D. Parra López C.A. Immunosenescence Study of T Cells: A Systematic Review Front. Immunol. 2021 11 3460 10.3389/fimmu.2020.604591 33519813 PMC7843425

184. Fahy G.M. Brooke R.T. Watson J.P. Good Z. Vasanawala S.S. Maecker H. Leipold M.D. Lin D.T.S. Kobor M.S. Horvath S. Reversal of Epigenetic Aging and Immunosenescent Trends in Humans Aging Cell 2019 18 e13028 10.1111/acel.13028 31496122 PMC6826138

185. Gao J. Zhao L. Wan Y.Y. Zhu B. Mechanism of Action of IL-7 and Its Potential Applications and Limitations in Cancer Immunotherapy Int. J. Mol. Sci. 2015 16 10267 10280 10.3390/ijms160510267 25955647 PMC4463645

186. Di Mitri D. Azevedo R.I. Henson S.M. Libri V. Riddell N.E. Macaulay R. Kipling D. Soares M.V.D. Battistini L. Akbar A.N. Reversible Senescence in Human CD4+CD45RA+CD27- Memory T Cells J. Immunol. 2011 187 2093 2100 10.4049/jimmunol.1100978 21788446

187. Aiello A. Farzaneh F. Candore G. Caruso C. Davinelli S. Gambino C.M. Ligotti M.E. Zareian N. Accardi G. Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention Front. Immunol. 2019 10 2247 10.3389/fimmu.2019.02247 31608061 PMC6773825

188. Mannick J.B. Morris M. Hockey H.-U.P. Roma G. Beibel M. Kulmatycki K. Watkins M. Shavlakadze T. Zhou W. Quinn D. TORC1 Inhibition Enhances Immune Function and Reduces Infections in the Elderly Sci. Transl. Med. 2018 10 eaaq1564 10.1126/scitranslmed.aaq1564 29997249

189. Weichhart T. Haidinger M. Katholnig K. Kopecky C. Poglitsch M. Lassnig C. Rosner M. Zlabinger G.J. Hengstschläger M. Müller M. Inhibition of MTOR Blocks the Anti-Inflammatory Effects of Glucocorticoids in Myeloid Immune Cells Blood 2011 117 4273 4283 10.1182/blood-2010-09-310888 21368289

190. El-Sherbiny Y.M. Meade J.L. Holmes T.D. McGonagle D. Mackie S.L. Morgan A.W. Cook G. Feyler S. Richards S.J. Davies F.E. The Requirement for DNAM-1, NKG2D, and NKp46 in the Natural Killer Cell-Mediated Killing of Myeloma Cells Cancer Res. 2007 67 8444 8449 10.1158/0008-5472.CAN-06-4230 17875681

191. Blom B. van Hoeven V. Hazenberg M.D. ILCs in Hematologic Malignancies: Tumor Cell Killers and Tissue Healers Semin. Immunol. 2019 41 101279 10.1016/j.smim.2019.06.002 31200953

192. Martín-Antonio B. Suñe G. Perez-Amill L. Castella M. Urbano-Ispizua A. Natural Killer Cells: Angels and Devils for Immunotherapy Int. J. Mol. Sci. 2017 18 1868 10.3390/ijms18091868 PMC5618517 28850071

193. Martín-Antonio B. Suñe G. Najjar A. Perez-Amill L. Antoñana-Vildosola A. Castella M. León S. Velasco-de Andrés M. Lozano F. Lozano E. Extracellular NK Histones Promote Immune Cell Anti-Tumor Activity by Inducing Cell Clusters through Binding to CD138 Receptor J. Immunother. Cancer 2019 7 259 10.1186/s40425-019-0739-1 31619273 PMC6794915

194. Carbone E. Neri P. Mesuraca M. Fulciniti M.T. Otsuki T. Pende D. Groh V. Spies T. Pollio G. Cosman D. HLA Class I, NKG2D, and Natural Cytotoxicity Receptors Regulate Multiple Myeloma Cell Recognition by Natural Killer Cells Blood 2005 105 251 258 10.1182/blood-2004-04-1422 15328155

195. Nersesian S. Schwartz S.L. Grantham S.R. MacLean L.K. Lee S.N. Pugh-Toole M. Boudreau J.E. NK Cell Infiltration Is Associated with Improved Overall Survival in Solid Cancers: A Systematic Review and Meta-Analysis Transl. Oncol. 2021 14 100930 10.1016/j.tranon.2020.100930 33186888 PMC7670197

196. Konjević G. Vuletić A. Mirjačić Martinović K. Colović N. Čolović M. Jurišić V. Decreased CD161 Activating and Increased CD158a Inhibitory Receptor Expression on NK Cells Underlies Impaired NK Cell Cytotoxicity in Patients with Multiple Myeloma J. Clin. Pathol. 2016 69 1009 1016 10.1136/jclinpath-2016-203614 27083212

197. Hanna J. Goldman-Wohl D. Hamani Y. Avraham I. Greenfield C. Natanson-Yaron S. Prus D. Cohen-Daniel L. Arnon T.I. Manaster I. Decidual NK Cells Regulate Key Developmental Processes at the Human Fetal-Maternal Interface Nat. Med. 2006 12 1065 1074 10.1038/nm1452 16892062

198. Jabrane-Ferrat N. Features of Human Decidual NK Cells in Healthy Pregnancy and During Viral Infection Front. Immunol. 2019 10 1397 10.3389/fimmu.2019.01397 31379803 PMC6660262

199. Fu B. Zhou Y. Ni X. Tong X. Xu X. Dong Z. Sun R. Tian Z. Wei H. Natural Killer Cells Promote Fetal Development through the Secretion of Growth-Promoting Factors Immunity 2017 47 1100 1113.e6 10.1016/j.immuni.2017.11.018 29262349

200. Sojka D.K. Yang L. Yokoyama W.M. Uterine Natural Killer Cells Front. Immunol. 2019 10 960 10.3389/fimmu.2019.00960 31118936 PMC6504766

201. Huhn O. Zhao X. Esposito L. Moffett A. Colucci F. Sharkey A.M. How Do Uterine Natural Killer and Innate Lymphoid Cells Contribute to Successful Pregnancy? Front. Immunol. 2021 12 607669 10.3389/fimmu.2021.607669 34234770 PMC8256162

202. Shah N. Martin-Antonio B. Yang H. Ku S. Lee D.A. Cooper L.J.N. Decker W.K. Li S. Robinson S.N. Sekine T. Antigen Presenting Cell-Mediated Expansion of Human Umbilical Cord Blood Yields Log-Scale Expansion of Natural Killer Cells with Anti-Myeloma Activity PLoS ONE 2013 8 e76781 10.1371/journal.pone.0076781 24204673 PMC3800010

203. Martin-Antonio B. Najjar A. Robinson S.N. Chew C. Li S. Yvon E. Thomas M.W. Mc Niece I. Orlowski R. Muñoz-Pinedo C. Transmissible Cytotoxicity of Multiple Myeloma Cells by Cord Blood-Derived NK Cells Is Mediated by Vesicle Trafficking Cell Death Differ. 2015 22 96 107 10.1038/cdd.2014.120 25168239 PMC4262774

204. Cai X. Zhang L. Wei W. Regulatory B Cells in Inflammatory Diseases and Tumor Int. Immunopharmacol. 2019 67 281 286 10.1016/j.intimp.2018.12.007 30572252

205. Zhou M. Wen Z. Cheng F. Ma J. Li W. Ren H. Sheng Y. Dong H. Lu L. Hu H.-M. Tumor-Released Autophagosomes Induce IL-10-Producing B Cells with Suppressive Activity on T Lymphocytes via TLR2-MyD88-NF-ΚB Signal Pathway Oncoimmunology 2016 5 e1180485 10.1080/2162402X.2016.1180485 27622036 PMC5006924

206. Zou Z. Guo T. Cui J. Zhang L. Pan L. Onset of Regulatory B Cells Occurs at Initial Stage of B Cell Dysfunction in Multiple Myeloma Blood 2019 134 1780 10.1182/blood-2019-128703

207. Zheng Y. Cai Z. Wang S. Zhang X. Qian J. Hong S. Li H. Wang M. Yang J. Yi Q. Macrophages Are an Abundant Component of Myeloma Microenvironment and Protect Myeloma Cells from Chemotherapy Drug-Induced Apoptosis Blood 2009 114 3625 3628 10.1182/blood-2009-05-220285 19710503 PMC2766678

208. Zheng Y. Yang J. Qian J. Qiu P. Hanabuchi S. Lu Y. Wang Z. Liu Z. Li H. He J. PSGL-1/Selectin and ICAM-1/CD18 Interactions Are Involved in Macrophage-Induced Drug Resistance in Myeloma Leukemia 2013 27 702 710 10.1038/leu.2012.272 22996336 PMC3652581

209. Wang H. Hu W. Xia Z. Liang Y. Lu Y. Lin S. Tang H. High Numbers of CD163+ Tumor-Associated Macrophages Correlate with Poor Prognosis in Multiple Myeloma Patients Receiving Bortezomib-Based Regimens J. Cancer 2019 10 3239 3245 10.7150/jca.30102 31289595 PMC6603386

210. Murray P.J. Macrophage Polarization Annu. Rev. Physiol. 2017 79 541 566 10.1146/annurev-physiol-022516-034339 27813830

211. Khalife J. Ghose J. Martella M. Viola D. Rocci A. Troadec E. Terrazas C. Satoskar A.R. Gunes E.G. Dona A. MiR-16 Regulates Crosstalk in NF-ΚB Tolerogenic Inflammatory Signaling between Myeloma Cells and Bone Marrow Macrophages JCI Insight 2019 4 129348 10.1172/jci.insight.129348 31593552 PMC6948777

212. Wang Q. Lu Y. Li R. Jiang Y. Zheng Y. Qian J. Bi E. Zheng C. Hou J. Wang S. Therapeutic Effects of CSF1R-Blocking Antibodies in Multiple Myeloma Leukemia 2018 32 176 183 10.1038/leu.2017.193 28626216 PMC5927777

213. Sun J. Park C. Guenthner N. Gurley S. Zhang L. Lubben B. Adebayo O. Bash H. Chen Y. Maksimos M. Tumor-Associated Macrophages in Multiple Myeloma: Advances in Biology and Therapy J Immunother. Cancer 2022 10 e003975 10.1136/jitc-2021-003975 35428704 PMC9014078

214. Favaloro J. Liyadipitiya T. Brown R. Yang S. Suen H. Woodland N. Nassif N. Hart D. Fromm P. Weatherburn C. Myeloid Derived Suppressor Cells Are Numerically, Functionally and Phenotypically Different in Patients with Multiple Myeloma Leuk. Lymphoma 2014 55 2893 2900 10.3109/10428194.2014.904511 24625328

215. De Veirman K. Van Ginderachter J.A. Lub S. De Beule N. Thielemans K. Bautmans I. Oyajobi B.O. De Bruyne E. Menu E. Lemaire M. Multiple Myeloma Induces Mcl-1 Expression and Survival of Myeloid-Derived Suppressor Cells Oncotarget 2015 6 10532 10547 10.18632/oncotarget.3300 25871384 PMC4496373

216. Lee S.-E. Lim J.-Y. Ryu D.-B. Kim T.W. Yoon J.-H. Cho B.-S. Eom K.-S. Kim Y.-J. Kim H.-J. Lee S. Circulating Immune Cell Phenotype Can Predict the Outcome of Lenalidomide plus Low-Dose Dexamethasone Treatment in Patients with Refractory/Relapsed Multiple Myeloma Cancer Immunol. Immunother. 2016 65 983 994 10.1007/s00262-016-1861-2 27342591 PMC11029332

217. Wang J. Veirman K.D. Beule N.D. Maes K. Bruyne E.D. Valckenborgh E.V. Vanderkerken K. Menu E. The Bone Marrow Microenvironment Enhances Multiple Myeloma Progression by Exosome-Mediated Activation of Myeloid-Derived Suppressor Cells Oncotarget 2015 6 43992 44004 10.18632/oncotarget.6083 26556857 PMC4791281

218. Uckun F.M. Dual Targeting of Multiple Myeloma Stem Cells and Myeloid-Derived Suppressor Cells for Treatment of Chemotherapy-Resistant Multiple Myeloma Front. Oncol. 2021 11 760382 10.3389/fonc.2021.760382 34858838 PMC8631522

219. Li K. Shi H. Zhang B. Ou X. Ma Q. Chen Y. Shu P. Li D. Wang Y. Myeloid-Derived Suppressor Cells as Immunosuppressive Regulators and Therapeutic Targets in Cancer Sig. Transduct. Target. Ther. 2021 6 362 10.1038/s41392-021-00670-9 PMC8497485 34620838