Advances and clinical applications of immune checkpoint inhibitors in hematological malignancies.

Abbreviations

antibody‐dependent cell‐mediated cytotoxicity

acute lymphoblastic leukemia

allogeneic hematopoietic cell transplantation

acute myeloid leukemia

antigen‐presenting cells

adult T‐cell leukemia‐lymphoma

autologous hematopoietic cell transplantation

B‐cell non‐Hodgkin lymphoma

Beta‐2‐microglobulin

bone marrow

bispecific T cell engager

body surface area

bispecific antibody

B and T lymphocyte attenuator

classic Hodgkin lymphoma

c‐myelocytomatosis viral oncogene homolog

chimeric antigen receptor T‐cell

cluster of differentiation

conventional DCs

cytokine‐induced killer

checkpoint inhibitory T cell‐engaging

chronic myeloid leukemia

acetyl coenzyme A

complete response rate

cytotoxic T lymphocyte‐associated antigen 4

dendritic cells

diffuse large B‐cell lymphoma

extra‐nodal natural killer/T cell lymphoma

European Society for Medical Oncology

crystalline fragment

Food and Drug Administration

follicular lymphoma

forkhead box protein P3

glycosyl‐phosphatidylinositol

human immunodeficiency virus

Hodgkin lymphoma

Heme oxygenase‐1

herpes virus entry mediator

immune checkpoint blockade

immune checkpoint inhibitors

interferon‐γ

immunoglobulin G

interleukin

immune‐related adverse events

Janus kinase

lymphocyte activation gene 3

leukocyte immunoglobulin‐like receptor subfamily B member 1

monoclonal antibodies

mantle cell lymphoma

myelodysplastic syndromes

major histocompatibility complex

multiple myeloma

messenger RNA

Mesenchymal stromal cells

natural killer cells

NK receptor group 2 member D

nanoparticles

objective response rate

oncolytic viruses

tumor necrosis factor receptor superfamily member 4 ligand

peripheral blood

primary central nervous system lymphoma

plasmacytoid DCs

programmed cell death protein 1

programmed cell death 1 ligand 1

progression‐free survival

poliovirus receptor‐associated immunoglobulin domain‐containing

poliovirus receptor‐related 2

relapsed/refractory

Richter syndrome

soluble CTLA‐4

signal regulatory protein α

soluble PD‐L1

T‐cell non‐Hodgkin lymphoma

tumor‐associated antigens

talimogene laherparepvec

transforming growth factor‐β

T cell immunoglobulin domain and mucin domain 3

Tumor necrosis factor‐alpha‐inducible protein 8‐like 2

tumor necrosis factor

regulatory T cells

V‐domain Ig suppressor of T cell activation

vesicular stomatitis virus

BACKGROUND

Immune homeostasis can be influenced by immune checkpoint molecules that are expressed on immune cells and tumor cells, which regulate the immune system, and targeting immune checkpoints could affect immune homeostasis [ 1 ]. Ligand‐receptor pairs that exert inhibitory effects on immune responses are referred to as immune checkpoint molecules. Additionally, the inhibitory pathways may uphold self‐tolerance and counteract the activation procedure to prevent excessive harm, which also promotes tumor cells to evade immune destruction, also called immune escape. In recent years, new advances in the mechanisms of tumor promotion by immune checkpoints have emerged continuously. For example, a new study demonstrates that programmed cell death protein 1 (PD‐1) signaling inhibits T‐cell tumors by restricting the production of glycolytic energy and acetyl coenzyme A (CoA) in a mouse model of T‐cell non‐Hodgkin lymphoma (T‐NHL) and tumor cells from patients with T‐NHL [ 2 ]. Monoclonal antibodies (mAbs) have been recognized as a means of immune checkpoint blockade (ICB), which could relieve the immune cells from suppression and enable them to identify and eliminate tumor cells [ 3 ].

Promising tumor immunotherapies known as immune checkpoint inhibitors (ICIs) have been recognized for their ability to enhance anti‐tumor immune responses by targeting immune checkpoints present on both immune cells and tumor cells [ 4 ]. A variety of ICIs targeting specific immune checkpoints are currently available in the clinic. In 2011, ipilimumab, the first block antibody against immune checkpoint cytotoxic T lymphocyte‐associated antigen 4 (CTLA‐4), was authorized for treating melanoma [ 5 ]. In 2014, the first PD‐1 targeting agent, pembrolizumab, was approved by U.S. Food and Drug Administration (FDA) for melanoma treatment [ 6 , 7 ]. In 2016, nivolumab, the first PD‐1 inhibitor approved to treat hematological malignancies, was approved for treating individuals with relapsed classic Hodgkin lymphoma (c‐HL) after autologous hematopoietic stem cell transplantation (auto‐HCT). In 2017, approval for the treatment of relapsed/refractory c‐HL (r/r c‐HL) was granted to pembrolizumab in 2017, after undergoing more previous treatment regimens [ 8 ]. At the present time, ICIs have become the most widely used anti‐tumor therapy [ 4 ], which have enhanced the clinical management of aggressive tumors, including improving patient survival, changing the way to assess efficacy and manage adverse effects, especially in metastatic melanoma [ 7 ]. Additionally, promising progress has been made in the application and research of ICIs independently and in combination with other drugs in hematological malignancies [ 9 , 10 ].

As numerous studies have verified the clinical significance and prognostic value of ICIs, the expressions of immune checkpoints may have the potential to become significant biomarkers in forecasting prognosis and responsiveness to ICIs. In addition to classical immune checkpoints like PD‐1 [ 11 ] and CTLA‐4 [ 12 ], emerging immune checkpoints have been gradually revealed to be prognostic biomarkers for tumors, including V‐domain Ig suppressor of T cell activation (VISTA) in extranodal natural killer/T‐cell lymphoma [ 13 ], lymphocyte activation gene 3 (LAG‐3) [ 14 ] in diffuse large B‐cell lymphoma (DLBCL).

Despite the promising future of ICIs, a considerable proportion of tumor patients fail to show a positive response to ICIs therapy or respond briefly before developing resistance, with significant variation among different types of tumors [ 15 ]. Perturbations of any steps of anti‐tumor immunity can contribute to ICIs resistance, including the recruitment and stimulation of T cells, the induction of T cell effector activities, and the formation of effector memory T cells [ 16 ]. The approaches to overcome drug resistance include focusing on other checkpoint molecules, enhancing T cell exposure to antigens, or combining ICIs with other therapeutic modalities, including cytokine therapies. ICIs treatment can lead to a range of immune‐related adverse events (irAEs) that collectively manifest as various side effects. The future application of ICIs in tumor treatment may involve predictive models that rely on the theory of integrated biomarker determination. Combination therapy presents new opportunities for the use of ICIs in tumor therapy, including oncolytic viruses (OVs) [ 17 ], neoantigen vaccines [ 18 ], bsAb [ 19 ], bio‐nanomaterials [ 20 ], tumor vaccines [ 21 ], and cytokine‐induced killer (CIK) cells [ 22 ].

Given the emerging research of immune checkpoints in the field of hematological malignancies in recent years, we focused on the current advances and potential clinical applications of ICIs in hematological malignancies, including the identification and utilization of biomarkers, the clinical studies of ICIs as standalone treatments or in combination, and the possible obstacles.

IMMUNE CHECKPOINTS IN DIFFERENT IMMUNE CELLS

Immune checkpoints, which have both similarities and differences on the surface of immune cells, antigen‐presenting cells (APCs), or tumor cells, have been extensively studied in the last decade [ 23 , 24 , 25 ]. Their types and distribution, which will be described separately in the following sections, are shown in Figure 1 .

Natural killer cells (NK cells)

NK cells, whose chief effector functions are cell killing and the releasement of pro‐inflammatory cytokine, can respond to virally infected cells [ 26 , 27 ].

Additional inhibitory immune checkpoints related to NK cells, apart from the inhibitory receptors linked to the major histocompatibility complex (MHC) class I, have been discovered, including the well‐known checkpoints like CTLA‐4, PD‐1, LAG‐3, and T cell immunoglobulin domain and mucin domain 3 (TIM‐3) [ 28 ]. Recent reports have identified B7‐ cluster of differentiation (CD) 28 family members, including B7‐H3, B7‐H7, and VISTA, as potential candidates for inhibiting NK cells. NK cell‐based immune checkpoint targets, including siglec‐7 and ‐9, CD200, and CD47, have recently been discovered within the siglec family receptors [ 28 ]. CD200 is regarded as a marker of tumor progression due to its elevated expression in different types of tumors in both non‐hematological [ 29 ] and hematological malignancies, including multiple myeloma (MM) [ 30 ] and acute myeloid leukemia (AML) [ 31 ]. Evidence suggests that the CD200‐CD200 receptor (CD200R) inhibitory pathway directly contributes to suppressing NK cells. The overexpression of CD200 in AML patients suppressed the anti‐tumor responses of NK cells, consequently elevating the likelihood of relapse in these individuals. These findings clearly demonstrated that the inhibition of NK cell cytotoxicity could be achieved by targeting cells that express CD200 [ 32 ], leading to immune escape and tumor progression.

Recently, a novel immune checkpoint signal regulatory protein α (SIRPα) was reported in NK cells, which could interact with target CD47 and counter other signals, such as interleukin 2 (IL‐2) and CD16. Overexpression of CD47 in the NK‐sensitive erythroleukemia cell line K562 significantly attenuated the killing of K562 by NK cells. Moreover, SIRPα deficiency or blockage increased the cytotoxic ability of rhesus monkey NK cells, which suggested that the disruption of the SIRPα‐CD47 immune checkpoint could enhance the immune response of NK cells against tumors and inhibit NK cell‐mediated tumor‐killing effects [ 23 ].

The formation of tumors has been linked to the existence of malfunctioning NK cells, including aberrant activation of inhibitory immune checkpoints [ 28 ]. Hence, ICIs that can restore the anti‐tumor activity of NK cells may serve as a viable choice for immunotherapy against tumors. In addition, combining anti‐PD‐1 or anti‐PD‐L1 inhibitors and NK cell‐specific checkpoint inhibitors, such as anti‐KIR or anti‐NKG2A inhibitors, can be used for combination immunotherapy in hematological malignancies based on checkpoint inhibition. With the development of novel checkpoints, combining these checkpoints for synergistic anti‐tumor responses is a future direction to fully utilize the tumor‐killing role of NK cells.

Regulatory T cells (Tregs)

Tregs have crucial functions in balancing immune homeostasis and suppressing autoimmune responses [ 33 ] because they can regulate T cells, B cells, NK cells, dendritic cells (DCs), and macrophages through both humoral and direct cell interactions [ 34 ]. However, Tregs impede immune surveillance against tumors in healthy patients and hinder the formation of potent immune responses against tumors in individuals with tumors by inhibiting the growth of cytotoxic CD8 + T cells [ 33 , 35 ]. Treg‐mediated suppression mechanisms encompass a range of molecules, including CTLA‐4, LAG‐3, IL‐10, IL‐35, IL‐2, forkhead box protein P3 (Foxp3), transforming growth factor‐β (TGF‐β), and others [ 36 ].

Previous studies have unveiled the impact of ICIs on T effector cells, but there is limited understanding regarding their influence on Tregs [ 33 ]. In a novel study, Bauer et al. [ 24 ] treated transgenic mice that spontaneously developed B cell lymphomas due to restricted overexpression of the proto‐oncogene c‐myelocytomatosis viral oncogene homolog ( c‐MYC ) in B cells with anti‐PD‐1 (clone J43) and anti‐CTLA‐4 (clone UC10‐4B9), resulting in reduced upregulation of Foxp3, CD25, and IL‐10 in Tregs, as well as a decrease in their inhibitory ability. During B cell lymphoma progression, intratumoral Tregs showed elevated expression of Foxp3, CD25, CTLA‐4, and IL‐10 compared to Tregs from healthy mice, which exhibited a positive association with heightened immunosuppressive capabilities. This function could be attributed to the change towards a pro‐inflammatory environment promoted by ICIs [ 24 ]. It has been reported that in c‐HL and NHL, such as DLBCL, ICIs therapy reduced the infiltration of immunosuppressive CD4 + /CD25 + /Foxp3 + Tregs [ 37 , 38 ]. As discussed above, targeting immune checkpoints on Tregs may offer a hopeful strategy for effective tumor immunotherapy.

DCs

DCs, B cells, and macrophages are typically regarded as the three significant groups of APCs. However, DCs can convey tumor antigens to the draining lymph nodes, thereby triggering the activation of T cells, an essential step for the development of T cell‐mediated immunity [ 39 ]. Conventional DCs (cDCs) especially excel in presenting exogenous and endogenous antigens to T cells and regulating the proliferation, survival, and effectiveness of T cells [ 40 ]. Antigens from tumor cells could be captured by cDCs and presented to T cells within the tumor microenvironment or when cDCs moved to lymph nodes connected to the tumor [ 41 ].

Although the response to PD‐1/programmed cell death 1 ligand 1 (PD‐L1) blocking can be promoted by anti‐TIM‐3 antibodies through reducing T cell exhaustion, the effectiveness of TIM‐3 blockade may extend to patients with tumors lacking significant T cell infiltration [ 42 ]. In co‐stimulatory molecules, CD80 and CD86 expressed by DCs controlled activation or suppression of T cells through the interaction between CD28 or CTLA4 [ 43 ]. Peng et al. [ 25 ] found that DCs infiltrating the expressed a high level of PD‐L1, which played a crucial role in limiting anti‐tumor immune responses. PD‐L1 expression on DCs was increased during antigen presentation in order to shield DCs from the cytotoxic effects of activated T cells. A high density of DCs has been correlated with favorable prognosis in c‐HL [ 44 ] and cutaneous T cell lymphoma (CTCL) [ 45 ]. Plasmacytoid DCs (pDCs), which are closely related to the AML and chronic myeloid leukemia (CML) progression, are hematopoietic cells, mainly developed from a myeloid branch including the macrophage DC progenitor with monocytes, cDCs and pDCs differentiation potential [ 46 ]. Therefore, although the mechanism behind immune checkpoints in DCs remains unclear, DCs still have the potential to act as target cells for ICIs to improve efficacy in tumor treatment.

Macrophages

Macrophages are an important cell type in the innate immune response, with CD47 serving as the main regulator for macrophages. Blocking CD47 allows macrophages to phagocytose leukemia cells for therapeutic purposes [ 47 ]. Since first confirmed as a tumor antigen in human ovarian tumors [ 48 ], CD47 has been progressively shown to be overexpressed in a wide range of hematological malignancies, such as acute lymphoblastic leukemia (ALL) [ 49 ], AML [ 50 ] and CML [ 51 ], which appears to be a universal indication for tumor cells to avoid phagocytosis by the innate immune system, particularly macrophages [ 52 ]. In addition, higher CD47 expression levels were negatively associated with good treatment response and prognosis in patients with acute myeloid leukemia and CML [ 51 ]. Previous studies have confirmed that CD47 messenger RNA (mRNA) and protein levels are higher in leukemic stem cells of AML patients than in normal healthy stem cells, and elevated CD47 was highly correlated with poor prognosis [ 49 ].

The involvement of CD47 in the tumor‐mediated evasion of phagocytosis was initially reported in cases of AML. Compared to normal cell counterparts, both mouse and human AML cells exhibited increased expression of CD47, which was directly linked to disease pathogenesis through the evasion of macrophages [ 53 ]. Consequently, clinical studies of CD47‐targeted agents have been underway for AML and myelodysplastic syndromes (MDS), either as monotherapy or in combination therapy. Macrophages exhibited strong phagocytosis of primary AML patient leukemic cells when exposed to the anti‐CD47 blocking antibody (clone B6H12), whereas the immunoglobulin G (IgG) control or a non‐blocking anti‐CD47 antibody did not show the same effect. Within 14 days of treatment, anti‐CD47 antibody treatment eliminated tumor cells of peripheral blood (PB) and bone marrow (BM) in primary AML patient‐derived xenografted mice in vivo. Furthermore, an anti‐CD47 antibody (magrolimab) that has been humanized for clinical purposes exhibited comparable elimination of leukemia and prolonged survival in vivo [ 54 ]. In addition to AML, similar pre‐clinical observations were noted in MDS patients [ 52 ].

Recently, new immune checkpoints have been identified in macrophages, including the cell surface glycoprotein CD137, also called 4‐1BB, which is a member of the tumor necrosis factor (TNF) receptor superfamily [ 55 , 56 ]. Stoll et al. [ 57 ] discovered that CD137 was expressed on circulating monocytes of healthy individuals and at even greater levels on cells derived from tumor patients. Monocytes that exhibit elevated levels of CD137 demonstrate enhanced ability to engulf MM and lymphoma cells treated with anti‐CD38 or anti‐CD20 mAbs, respectively, due to their heightened phagocytic capacity for antibody‐dependent phagocytosis [ 57 ]. Therefore, CD137 was identified as a new potential immune checkpoint on human macrophages, suggesting possible therapeutic benefits in the treatment of tumors.

In summary, tumor cells mediate immune escape through various immune checkpoints located on the surface of immune cells, and ICIs targeting these immune checkpoints may have better efficacy. In addition, cellular immunotherapies are evolving in hematological malignancies as novel therapies, mainly including chimeric antigen receptor T‐cell (CAR‐T) therapy, NK‐cell‐based immunotherapy (CAR‐NK therapy), and allogeneic hematopoietic stem cell transplantation (allo‐HSCT). DC vaccines are also being experimented in murine T cell lymphoma models [ 58 ] and AML patients [ 59 ]. Therefore, both immune cells themselves and ICIs targeting immune checkpoints of immune cells have great therapeutic potential in hematological malignancies. Meanwhile, combining ICIs with targeted immune cell chemotherapeutic agents is a promising strategy to improve the treatment response rate of hematological malignancies.

APPLICATION OF IMMUNE CHECKPOINTS IN HEMATOLOGICAL MALIGNANCIES

ICIs have been rapidly developed in solid tumors while are less effective in hematological malignancies, which has been rapid progress in recent years. However, numerous unsatisfactory clinical problems still need to be solved in the application of ICIs due to immature technology and other reasons, such as resistance and adverse effects. In recent years, there has been a growing focus on researching immune checkpoints, including biomarkers, combination therapies with ICIs, resistance, and toxicities.

Prognostic biomarkers

The lack of specific biomarkers for prognostic stratification and accurate diagnosis makes hematological malignancies the most challenging type of tumor to diagnose. It is worth noting that researchers have proved that immune checkpoints could be used as promising biomarkers for diagnosis and prognosis prediction in hematological malignancies.

PD‐1/PD‐L1

According to recent research, higher levels of immune checkpoints have been linked to poor prognosis and worse treatment efficacy in hematological malignancies. For example, PD‐1 and PD‐L1 expression were poor prognostic indicators in patients with aggressive adult T‐cell leukemia‐lymphoma (ATLL) [ 12 ]. Cuccaro et al. [ 11 ] found that increased PD‐L1 expression in PB was associated with advanced disease, systemic symptoms, and inferior progression‐free survival (PFS) in HL patients, which proved that PD‐L1 expression in PB might be a potential indicator for prognosis in HL. High PD‐1/PD‐L1 expression was associated with poor prognosis in aggressive acquired immunodeficiency syndrome (AIDS)‐associated non‐Hodgkin's lymphoma (NHL) [ 60 ]. The high level of CD4 + PD1 + and CD8 + PD1 + T lymphocytes were both prognostic factors of AML patients and ALL patients [ 61 ]. Elevated levels of soluble PD‐L1 (sPD‐L1) were associated with poor prognosis in MM [ 62 ].

In addition to prognostic markers, the researchers explored the potential of PD‐1 and PD‐L1 as biomarkers in predicting treatment response, testing safety, and detecting disease progression [ 63 , 64 , 65 ]. In research for cutaneous T cell lymphoma, PD‐1 + T cells were involved in the formation of spatial biomarkers that could be strongly associated with response to pembrolizumab treatment [ 65 ]. In another study, by quantifying PD‐1 in patients with FL and those who converted to DLBCL, researchers found that high levels of PD‐1 in the follicles were associated with a significantly shorter time to transformation‐free survival, indicating that PD‐1 expression in follicular lymphoma (FL) tumor tissues prior to treatment could be used as a risk‐predictive biomarker for transformation to DLBCL [ 63 ]. Through analysis of metabolic markers on immune cells from lymphoma patients undergoing autologous transplantation, including DLBCL, FL, and T‐NHL, other researchers found that lymphoma patients with a sustained increase in PD‐1 expression on T cells had a shorter median survival after autologous transplantation, suggesting that PD‐1 expression on T cells could be used as an unfavorable biomarker for lymphoma patients undergoing autologous transplantation [ 64 ].

All of the above studies suggested that PD‐1 and PD‐L1 may serve as potential biomarkers in hematological malignancies. Based on these results, a large number of studies have come to explore the potential of targeting PD‐1 and PD‐L1 for the treatment of hematologic malignancies. However, since the therapeutic effect of anti‐PD‐1/PD‐L1 therapy varies considerably in hematological malignancies with high heterogeneity, it is necessary to detect the expression level of PD‐1 and PD‐L1 to decide whether to use ICIs targeting PD‐1 and PD‐L1, as well as to predict their therapeutic responses. Furthermore, larger sample size experiments need to be used to validate their potential as prognostic markers for hematological malignancies.

CTLA‐4

CTLA‐4 has been reported to be a poor prognostic indicator in patients with aggressive ATLL [ 12 ]. Previous analysis indicated that unsuitable manifestation of CTLA‐4 on CD4 + T cells in active MM was linked to unfavorable clinical outcomes. MM patients with decreased CTLA‐4 levels expression may be prone to experiencing early relapse [ 66 ]. In a research on MDS patients, soluble CTLA‐4 (sCTLA‐4) levels were higher in MDS patients compared to controls, and sCTLA‐4 levels were significantly higher in patients with high‐risk MDS compared to the intermediate‐risk group [ 67 ]. The higher the patient's CTLA‐4 levels, the higher the risk of transformation to AML and the higher the mortality rate after follow‐up, suggesting that elevated sCTLA‐4 levels in MDS patients are an indicator of poor prognosis in MDS [ 67 ]. In another study of AML patients, the mRNA expression of CTLA‐4 was significantly upregulated in AML patients compared to healthy controls. In addition, CTLA‐4 expression was found to be associated with poor prognosis, and regression analysis revealed that CTLA‐4 expression level was an independent predictor of prognosis in AML patients [ 68 ].

Based on these results, a large number of studies have begun to explore the potential of targeting CTLA‐4 for the treatment of hematological malignancies, with promising results. However, similar to the results of anti‐PD‐1/PD‐L1 therapy, anti‐CTLA‐4 therapy in hematological malignancies has shown markedly variable results. For example, in a phase 1 clinical study of ipilimumab in B‐cell non‐Hodgkin lymphoma (B‐NHL) patients, the complete response rate (CRR) was only 5.6% [ 69 ]. However, in another phase 1 clinical study of ipilimumab in allo‐HSCT patients, the CRR could reach 23% [ 70 ]. Therefore, in order to confirm the potential of CTLA‐4 as a prognostic biomarker in hematological malignancies, it is necessary to conduct studies with a larger sample size.

TIM‐3

In addition, microenvironmental expressions of TIM‐3 were strongly correlated with better overall survival, which were important prognostic factors in patients with ATLL [ 71 ]. NK cells play a crucial role in immune responses against AML, and the expression of TIM‐3 is significantly high in NK cells derived from AML individuals, which is associated with enhanced functional authorization and superior capabilities as effectors. Racova et al. [ 72 ] constructed prognosis‐related biomarkers of active immunity against AML by NK cell frequency and TIM‐3 expression levels. Similarly, Tim‐3 + Foxp3 + Treg cells were highly enriched in the tumor microenvironment (TME) of DLBCL patients, which were correlated with the poor prognosis [ 73 ]. In addition to prognostic biomarkers, TIM‐3 has potential as a biomarker for predicting chemotherapy efficacy. In a study of DLBCL patients, TIM‐3 expression was increased in CD3 + T cells from DLBCL patients compared to healthy controls, and the level of TIM‐3 expression was decreased after four courses of standard chemotherapy. Patients with low TIM‐3 expression had a higher treatment efficacy than patients with high TIM‐3 expression, indicating that TIM‐3 may serve as a potential indicator of chemotherapy efficacy in DLBCL patients [ 74 ]. Another study also demonstrated that, after three years of follow‐up, the rate of Tim‐3 positive expression was higher in treatment‐effective DLBCL patients than in treatment‐ineffective patients, and Tim‐3 positivity was an independent risk factor for the prognosis of DLBCL [ 75 ].

Collectively, TIM‐3 has the potential to serve as a potential biomarker for hematological malignancies. Furthermore, we need more research with larger sample sizes to demonstrate the ability of TIM‐3 as a biomarker and the reliability of predicting treatment efficacy for different hematological malignancies.

Others

In addition to the above familiar immune checkpoints, novel immune checkpoints are constantly being identified as potential biomarkers in hematological malignancies. For example, microenvironmental expressions of tumor necrosis factor receptor superfamily member 4 ligand (OX40L) were strongly correlated with better overall survival, which were important prognostic factors in patients with ATLL [ 71 ]. Moreover, AML patients with high levels of OX40L expression on tumor cells had significantly worse survival than patients with low OX40 expression, suggesting OX40 was a novel prognostic marker for AML patients [ 76 ].

Several studies have demonstrated that high expression of LAG‐3 was correlated with worse outcomes and functioned as an independent prognostic indicator in DLBCL and MDS patients [ 14 , 77 , 78 ]. Moreover, VISTA was an independent prognostic factor for patients with extra‐nodal natural killer/T cell lymphoma (ENKTCL), providing that VISTA could be a promising immune biomarker to perform prognostic stratification or diagnosis for ENKTCL [ 13 ].

Another study in AML patients showed an imbalance in the distribution of TIGIT and CD226 (the competitive co‐stimulatory receptor for TIGIT) on γδ T cells, with a decrease in CD226 + γδ T cells and an increase in TIGIT + γδ T cells in patients with de novo AML, whereas TIGIT‐CD226 + γδ T cells were restored in patients with AML who reached complete response after chemotherapy [ 79 ]. In addition, non‐M3 AML patients with higher TIGIT + CD226 − γδ T cells had lower overall survival [ 79 ].

Tumor necrosis factor‐alpha‐inducible protein 8‐like 2 (TIPE2) is a newly identified negative regulator of anti‐tumor immunity that plays a crucial function in preserving immune homeostasis. It has been shown in pan‐cancer studies that TIPE2 might be a promising immune checkpoint biomarker in different hematological malignancy types, including AML, and might serve as a promising target for immunotherapy [ 80 ]. The high expression of the novel immune checkpoint molecule, siglec‐15, on peritumoral macrophage predicted the positive outcome in primary central nervous system lymphoma (PCNSL), indicating that siglec‐15 might represent an independent prognostic factor [ 81 ].

Taken together, immune checkpoints have been demonstrated to be prognostically relevant in hematological malignancies, particularly in lymphoma and leukemia, which potentially improve the prognosis and stratification accuracy. In addition, a large amount of prognosis‐related statistics could help researchers make useful references for the development of new ICIs and select the immune targets and directions for research and development. Immune checkpoints are no longer to be used merely as prognostic biomarkers for hematological malignancies, and new studies have expanded to explore their potential as biomarkers for safety and clinical outcomes. There are individualized differences in the efficacy of ICIs among patients with hematological malignancy, so more experiments with larger sample sizes are needed to repeatedly validate the ability of immune checkpoints to be clinical biomarkers. Meanwhile, two or more immune checkpoints have been found to be concurrently associated with the prognosis in hematological malignancies and may have a synergistic effect, which also provides a mechanistic basis for the subsequent combined application of ICIs targeting different immune checkpoints.

The advances of ICIs in hematological malignancies

A variety of ICIs targeting specific immune checkpoints have been currently available in the clinic, including anti‐CTLA‐4 and anti‐PD‐1 [ 82 ]. Recent clinical studies on ICIs in hematological malignancies are shown in Table 1 .

PD‐1/PD‐L1

A phase II study evaluated pembrolizumab for r/r c‐HL patients in complete response who discontinued treatment and subsequently experienced partial response were eligible for second‐course pembrolizumab, and objective response rate (ORR) was achieved in 71.4%, while CRR was achieved in 27.6% [ 83 ]. In another single‐arm phase II study of pembrolizumab in individuals with r/r HL, ORR was 69.0%, and CRR was 22.4% [ 84 ], while another similar phase II trial showed 60% ORR [ 10 ]. According to the trials above, the ORR of pembrolizumab for r/r HL was approximately 60% [ 85 ]. However, a phase Ib study of pembrolizumab showed an ORR of 0% in r/r MM [ 86 ]. Moreover, in a phase II trial to evaluate the effectiveness of nivolumab in r/r FL patients, the ORR was 4% [ 87 ]. A phase II study of nivolumab in r/r c‐HL after auto‐HCT demonstrated an ORR of 69% [ 88 ]. Another phase I trial evaluated the efficacy of nivolumab, with ORR of 40%, 36%, and 40% observed in individuals diagnosed with FL, DLBCL, and peripheral T‐cell lymphoma, and adverse events occurred in 51 (63%) patients [ 89 ]. A prospective phase I clinical trial of nivolumab for relapsed hematological malignancies, including chronic lymphocytic leukemia (CLL), HL, MM, AML, ALL, MDS, and CML, after allo‐HCT showed an ORR of 32% [ 90 ]. A phase Ia/Ib study evaluated the primary anti‐tumor effects of GLS‐010, a monoclonal antibody that specifically inhibited the PD‐1/PD‐L1 axis, in patients with refractory lymphoma, and the ORR was 23.6% [ 91 ]. A study of anti‐PD‐1 efficacy in pediatric malignancies showed that the survival rate of pediatric patients with HL was the highest among pediatric malignancies when pembrolizumab was used alone or when nivolumab was combined with brentuximab vedotin, a CD30‐directed antibody‐drug conjugate linked to monomethyl auristatin E [ 92 ]. Another study of anti‐PD‐1 efficacy in pediatric hematological malignancies demonstrated that nivolumab plus brentuximab vedotin was an effective and safe treatment for inducing remission in pediatric r/r c‐HL patients [ 93 ]. In conclusion, ICIs targeting PD‐1 and PD‐L1 could exert anti‐tumor effects in hematological malignancies. However, both response rates and efficacy differed in the treatment of hematological malignancies. Moreover, a significant proportion of patients with hematological malignancies do not respond well to ICIs therapy. Therefore, subsequent studies are needed to explore the resistance mechanisms of ICIs targeting PD‐1 and PD‐L1, identify more effective markers for medicine guidance, and explore more effective combination strategies in hematological malignancies.

TIM‐3

TIM‐3 is still a newly identified target for ICIs with numerous active early‐phase trials. A phase I trial investigated Sym023 as monotherapy for lymphoma. According to initial data, individuals who received the maximum dosage of Sym023 reported an ORR of 66.7% within a treatment duration of 16 weeks ( NCT03489343 ). In a phase II trial ( NCT04623216 ), an anti‐TIM‐3 agent sabatolimab (MBG4530) was assessed as a monotherapy or in combination with azacitidine to enhance the graft‐vs‐leukemia effectiveness in AML patients who received allo‐HCT and achieved CR. Moreover, NCT04266301 , NCT03066648 and NCT05367401 are evaluating the efficacy of sabatolimab along with other treatments for MDS, CLL and AML. A phase I study, NCT05357651 , is assessing a bsAb, LB1410 (anti‐PD‐1/anti‐TIM‐3), in the treatment of lymphoma. NCT05216835 is another phase I trial that evaluated anti‐PD‐1 and anti‐TIM‐3 bsAb (AZD7789) in r/r HL patients. Another phase I is an open‐label clinical trial to evaluate the efficacy of TQB2618 injection, an inhibitor of TIM‐3, combined with penpulimab in individuals with r/r lymphoma ( NCT05400876 ). Moreover, in NCT03311412 , the researchers further assessed anti‐PD‐1 (Sym021) therapy in combination with Sym022 or anti‐TIM‐3 (Sym023) in lymphoma.

LAG‐3

Ongoing active trials about LAG‐3 include NCT05078593 , a phase I trial investigating HLX26, an anti‐LAG‐3 agent, to evaluate the safety and tolerability in lymphomas. Another phase I, open‐label trial NCT03489369 , evaluated the anti‐tumor activity of an anti‐LAG‐3 mAb (Sym022) in lymphomas. A phase II trial, NCT04913922 , is examining the potential of combining relatlimab, nivolumab, and azacytidine as a therapy for AML, lymphoma, and NHL. Another phase II trial ( NCT04150965 ) was conducted to evaluate anti‐LAG‐3 (relatlimab) and anti‐TIGIT (BMS‐986207) to assess their effectiveness as single agents or when combined with pomalidomide and dexamethasone. Furthermore, LAG‐3 protein was highly expressed on malignant Richter syndrome (RS) cells and tumor‐infiltrating lymphocytes, supporting the possibility of LAG3 inhibition to enhance anti‐tumor responses in RS [ 94 ]. LAG‐3 studies have also focused on the efficacy, safety, and tolerability of ICIs. Large sample‐size studies are still needed to investigate drug resistance and potential biomarkers. Most of the clinical trials on ICIs targeting LAG‐3 in hematological malignancies are still under investigation, and few results have been reported.

TIGIT

In addition to numerous classic ICIs in clinical trials [ 83 , 84 ], numerous novel targets have been investigated with positive results. A novel study demonstrated that TIGIT was widely expressed on lymphoma‐infiltrating T cells (LITs) in a variety of human lymphomas and was frequently co‐expressed with PD‐1 [ 95 ]. Moreover, in a syngeneic A20 B‐cell lymphoma mouse model, blockade of PD‐1 or TIGIT alone retarded tumor progression. In contrast, simultaneous blockade of PD‐1 and TIGIT resulted in complete rejection and significantly prolonged survival, providing a rationale for research on TIGIT and PD‐1 blockade in lymphoma [ 95 ]. In addition, another study on the expression of TIGIT in biopsy tissues of human hematologic malignancies showed that chronic lymphocytic leukemia/small lymphocytic lymphoma and anaplastic large cell lymphoma demonstrated high TME TIGIT expression compared with PD‐L1, with a high proportion of dual TIGIT and PD‐L1‐positivity, which is likely to contribute to the design and correlative study of therapeutic response in clinical trials targeting TIGIT alone or in combination with PD1/PDL1 [ 96 ].

Leukocyte immunoglobulin‐like receptor subfamily B member 1 (LILRB1)

LILRB1, widely expressed in human immune cells, is an inhibitory patterned receptor based on the immune receptor tyrosine whose ligands, such as MHC‐I molecules, could activate LILRB1 and transmit inhibitory signals, thereby suppressing the immune response. Chen et al. [ 97 ] discovered that the proportion of LILRB1 + NK cells was higher in patients with MM after treatment compared to that in healthy donors. Furthermore, specific antagonistic anti‐LILRB1 monoclonal antibodies developed by them enhanced the anti‐tumor activity of NK cells against various hematological malignancies, including MM, leukemia, and lymphoma, suggesting that LILRB1 blockade on immune effector cells like NK cells may offer a new approach in anti‐tumor therapy [ 97 ]. Furthermore, dual blockade of crystalline fragment (Fc)‐silencing antibodies (LILRB1‐IgGσ and LILRB2‐IgGσ) against LILRB with CD47 antibodies enhanced antibody‐dependent cellular phagocytosis (ADCP) by macrophages and improved treatment effect of CD20 antibody therapy in CLL and lymphomas, whereas LILRB blockers alone were ineffective [ 98 ].

Others

Extensive research has been conducted on CD24, a highly glycosylated protein attached to cell membranes through glycosyl‐phosphatidylinositol (GPI) anchor [ 99 ]. Freile et al. [ 100 ] found that CD24 was heavily expressed on mantle cell lymphoma (MCL) cells, and the therapy with CD24 mAbs was more effective compared to CD47 mAbs in MCL, suggesting that CD24 was a promising immunotherapeutic target in MCL patients.

A study revealed the role of new immune checkpoint B and T lymphocyte attenuator (BTLA) and its ligand herpes virus entry mediator (HVEM) in suppressing immune responses mediated by NK cells and its association with poor prognosis in CLL [ 101 ]. BTLA blockade reduced CLL cells and enhanced NK cell‐mediated responses ex vivo by increasing interferon‐γ (IFN‐γ) production, cytotoxic capability, and antibody‐dependent cell‐mediated cytotoxicity (ADCC), indicating that the BTLA may be a promising target for CLL [ 101 ].

The poliovirus receptor‐associated immunoglobulin domain‐containing (PVRIG) is a novel immune checkpoint whose ligand is poliovirus receptor‐related 2 (PVRL2) [ 102 ]. The inhibition of PVRIG greatly enhanced NK cell killing of PVRL2 + AML cells. Therefore, the PVRIG‐PVRL2 pathway can be targeted with PVRIG‐blocking antibodies for NK‐mediated immunotherapy of PVRL2 + AML [ 102 ].

In summary, most of the clinical trials are still focused on approved and marketed drugs, and due to the presence of adverse effects and drug resistance, how to control the dose and increase the efficacy by combining with other chemotherapeutic agents is the focus of the research. In addition, new ICIs targeting old and new immune checkpoints are also being actively put into clinical trials, and some of them have already achieved encouraging results. Concurrent basic research and clinical studies of new immune checkpoints and ICIs can effectively promote their clinical application, thereby benefiting more patients with hematological malignancies in the future. Moreover, large sample size experiments are needed to further validate the predictive ability of immune checkpoint expression on drug efficacy and explore the mechanism of drug resistance to ICIs in hematological malignancies, which are the aspects lacking in the current studies.

Human immunodeficiency virus (HIV)‐infected patients, as well as those with congenital immunosuppression, are far more likely to develop hematological malignancies such as HL than the general population [ 103 ]. However, compared with people living without HIV, people living with HIV and tumors have traditionally been excluded from ICI trials. Therefore, there is a paucity of real‐world data on the use of ICIs in people living with HIV and tumors [ 104 ]. Recently, newer retrospective and prospective studies have shown that ICIs are a safe and effective cancer treatment for people with HIV. Numerous studies have shown that HIV patients with hematological malignancies, including HL and NHL, who received ICIs, such as anti‐PD‐1 and anti‐CTLA‐4 drugs, generally tolerated the drugs well [ 105 ]. Considering that hematological malignancy patients with HIV infection are inherently immunosuppressed, previous treatment regimens and dosages of ICIs may no longer be applicable and lead to more serious side effects. Therefore, the irAEs in patients with specific underlying diseases, such as AIDS, should be given extra attention. We need more data to compare the safety of ICIs in this population. Lurain K et al. [ 106 ] reported that the response rate of pembrolizumab was up to 50% in patients with HIV‐associated NHL. Moreover, ICIs therapy not only provided relief from cancer in HIV‐infected individuals but also served as a therapeutic intervention to restore the immune response to HIV, reverse HIV latency, and achieve a functional cure for HIV infection [ 107 ].

Combination of ICIs with other therapies

As a single therapy, the effectiveness of ICIs is restricted due to a low rate of response and immune‐related side effects, and combination therapies provide new opportunities for the application of ICIs in tumor therapy. This section briefly describes several avenues combined with ICIs and other therapies.

OVs

OVs have emerged as another therapeutic agent for tumor treatment. Combining OVs and ICIs could improve outcomes, which may be related to the mechanism of CD8 + T cell infiltration and enhanced IL‐1α expression [ 108 ]. For immune ‘cold tumors’, the efficacy of ICIs is poor, and OVs can stimulate the tumor immune microenvironment to improve the anti‐tumor effect of ICIs, so the combination of ICIs and OVs can have a synergistic effect on the enhancement of anti‐tumor immunity. OVs are mostly utilized for research in tumor treatment in combination with ICIs, and vesicular stomatitis virus (VSV) has also been demonstrated to be effective in hematological malignancies models, such as ALL [ 109 ] and c‐HL [ 110 ] combined with ICIs. Shen et al. [ 17 ] illuminated that the combination of VSV and anti‐PD‐L1 antibody enhanced therapeutic outcomes in murine AML. A recent study has also explored the improvement of CAR‐T cell responses in B cell lymphoma through the use of lysosomal viral therapies that also target 4‐1BB, a novel immune checkpoint as an inducible costimulatory receptor [ 111 ]. Similarly, an immunostimulatory Lokon oncolytic adenovirus (LOAd) targeting 4‐1BB has been used to evaluate the efficacy of treating MM, with encouraging results from cell experiments [ 112 ]. Moreover, there are also a series of ongoing experiments. A phase I clinical study ( NCT03605719 ) has combined nivolumab and pelareorep (AN1004) to treat recurrent plasma cell myeloma. Another phase I clinical study combined ipilimumab, nivolumab, and recombinant VSV to treat B‐NHL, T‐NHL, AML, MDS, and MM. A phase II trial ( NCT02978625 ) of talimogene laherparepvec (T‐VEC) combined with nivolumab was performed in treating patients with refractory lymphomas such as T cell and NK cell lymphoma, anaplastic large cell lymphoma, and Sezary syndrome, etc. In summary, the combination of OVs and ICIs has a promising perspective on hematological malignancies. OVs are also one of the therapies with the highest number of ongoing clinical trials of combination therapies with ICIs.

Neoantigen vaccines

Neoantigens resulting from tumor‐specific somatic alterations are more favorable therapeutic targets compared to traditional tumor‐associated antigens (TAAs) like NY‐ESO‐1 and MUC‐1. This is due to the ongoing difficulties in developing vaccines targeting TAAs, which raise concerns about potential autoimmunity [ 113 ]. Tumor‐specific neoantigens formed by somatic mutations in tumor cells are generally not immune‐tolerant and are, therefore, considered to be highly promising therapeutic targets for tumor vaccines. Both tumor vaccines and ICIs therapies can exert anti‐tumor effects by expanding and/or inducing maintenance of tumor‐specific T cells. A multidimensional comparative study revealed that the neoantigen vaccines combined with ICBs had a stronger ability to activate the immune response than either the vaccines or ICBs alone [ 114 ]. At the same time, ICIs therapy, together with neoantigen vaccines, could successfully induce anti‐tumor‐specific T cell immunity while reducing the probability of triggering immune‐related adverse events [ 113 ]. Nevertheless, the neoantigen vaccine alone exhibited a restricted anti‐tumor impact, as no tumor regression was detected. Meanwhile, based on the results that PD‐1 and TIM‐3 expression was elevated on neoantigen‐specific T cells, immunosuppressive TME could limit the effectiveness of neoantigen vaccination by manipulating the functional states of T cells, possibly through the PD‐L1/PD‐1 [ 113 ]. After being treated with the combination of ICIs and vaccines, complete tumor regression and substantial enhancement survival were observed [ 113 ]. These findings suggested that combining ICIs with the neoantigen vaccine could greatly enhance its anti‐tumor efficacy. Research on neoantigen vaccines is currently focused on solid tumors, but there has been a gradual rise in hematological malignancies in recent years, including AML [ 115 ], T cell lymphoma [ 18 ] and MM ( NCT03631043 ). Further investigation is needed to explore the potential value of combining neoantigen vaccines with ICIs in treating hematological malignancies.

BsAb

BsAb therapy is a type of tumor immunotherapies currently approved for clinical application [ 116 ]. BsAb enhances the ability of T cells to kill tumor cells by connecting T cells and tumor antigens [ 117 ]. Combining ICIs and bsAb has the potential to overcome the resistance to ICIs immunotherapy. The approval for the treatment of ALL was granted to blinatumomab, a bispecific T cell engager (BiTE) that targets both CD19 and CD3 in 2014 [ 116 ]. Most anti‐CD3 pan‐T cell engagers have been developed to treat hematological malignancies, such as targeting CD20 for NHL and targeting B cell maturation antigen for MM [ 118 , 119 ]. Unfortunately, ongoing clinical trials found that only a limited proportion of individuals can benefit from bsAb therapy. T cell anergy and exhaustion is a main obstacle caused by inhibitory immune checkpoint pathways, including the PD‐L1/PD‐1 axis [ 87 ]. As the use of bsAb essentially lead to strong T cell activation and production of proinflammatory cytokines [ 120 ], such therapies might also trigger tumor cells to employ immunosuppressive strategies to escape antibody‐mediated cell lysis. For instance, CD33/CD3 BiTE antibody treatment could induce high expression of PD‐L1 on AML cells, which could lead to T‐cell‐induced immune escape [ 121 ]. Enlightened by the inhibitory function of PD‐1/PD‐L1 pathway in AML, a cellular experiment combining PD‐1/PD‐L1 blockade with CD33/CD3 BiTE antibody showed enhanced T cell proliferation and IFN‐γ production, which resulted in enhanced AML cells lysis [ 121 ]. Moreover, a bifunctional checkpoint inhibitory T cell‐engaging (CiTE) antibody was found to induce complete AML eradication in a mice xenograft model [ 19 ]. Currently, bsAb, which engages patient's T cells or NK cells to combat tumor cells, is gaining interest in the treatment of hematological malignancies.

Bio‐nanomaterials

The progress made in nanotechnology has played a crucial role in the creation of effective, secure, and productive drug systems against tumors based on nanoparticles (NPs). Studies have demonstrated that ICIs delivered by NPs can improve the effectiveness of T cell‐focused immunotherapy [ 122 , 123 ]. Currently, novel ICIs have been used to investigate whether they can bind to NPs to enhance the efficacy of ICIs themselves. For example, Heme oxygenase‐1 (HO‐1), an antioxidant and immunosuppressive enzyme expressed in many types of tumors, has been considered a potential target in the context of a chemotherapy‐induced anti‐tumor immune response [ 20 , 124 ]. Yong et al. [ 20 ] conducted a study where a hybrid nanoparticle consisting of lipids and polymers (hNP) was utilized to carry mesoporphyrin (SnMP), an inhibitor of HO‐1. Additionally, the hNP was modified with an engineered antibody to enable targeted delivery to leukemic cells. HO‐1‐inhibiting T‐hNP improved the sensitivity of human leukemia cells to chemotherapy in a mouse model of AML [ 20 ]. This novel therapeutic approach for AML showed promising potential [ 20 , 125 ], and considering the pharmacokinetic mechanism of the bio‐nanomaterials and their metabolism through the liver, the following clinical trials will most likely focus on reducing the liver damage of this drug as well as investigating new drug delivery systems [ 125 ]. The findings also provide fresh ideas for nanotechnology to be used in combination with ICIs in treating hematological malignancies.

Other therapies

Mesenchymal stromal cells (MSCs) have been used as new vaccine carriers. Unlike neoantigen vaccines, Abusarah et al. [ 21 ] constructed a vaccination strategy by utilizing engineered MSCs to express the immunoproteasome complex (MSC‐IPr). The ability of MSC‐IPr to present a significantly diverse epitope repertoire resulted in a strong reactivation of T cell immunity against lymphoma [ 21 ]. Vaccination of mice T cell and B cell lymphoma models effectively controlled tumor progression and combined with antibodies targeting PD‐1, CTLA‐4, LAG‐3, or 4‐1BB under autologous and allogeneic settings could enhance its effects, demonstrating that MSC‐IPr constitutes a hopeful subgroup of non‐blood‐related APCs suitable for creating universal cell‐based tumor vaccines, and it is also promising to enhance the efficacy by combining those vaccines with ICIs [ 21 ].

CIK cells, a heterogeneous subset of T lymphocytes expanded outside the body, primarily exert their cytotoxic effects by recognizing NK receptor group 2 member D (NKG2D) instead of the T cell receptor [ 126 ]. They also display tumor‐killing abilities, thereby aiding in the prolonged survival of individuals with tumors [ 127 ]. When CIK cells came into contact with B‐NHL cells, the expression of PD‐1 on CIK cells and PD‐L1 on tumor cells were both upregulated, suggesting that CIK had the potential to be used in combination with ICIs targeting PD‐1/PD‐L1 [ 128 ]. The use of CIK cells in research on AML [ 129 ], CML [ 130 ], and CLL [ 22 ] has already been demonstrated to be an innovative clinical perspective. Data from a current study showed that the survival rate in two NHL cell lines (DAUDI and SU‐DHL‐4) was significantly affected when they were co‐cultured with CIK cells activated by PD‐1 blockade. In a word, the combination of PD‐1 inhibitors and CIK cells could offer a therapeutic alternative for NHL [ 128 ].

Numerous studies have evaluated innovative combinations of targeted therapies, epigenetic therapies, and immunotherapy treatments to improve treatment response and combat drug resistance [ 131 ]. For example, HBI‐8000 is a novel orally bioavailable class I selective histone deacetylase inhibitor that directly alters anti‐tumor activity by inducing apoptosis in adult T‐cell lymphoma patients, among other mechanisms. Bissonnette et al. [ 132 ] treated mice bearing syngeneic B‐cell lymphoma daily with HBI‐8000, either by itself or in conjunction with PD‐1, PD‐L1, or CTLA‐4 antibodies. The results showed that the activity of ICIs antibodies targeting these immune checkpoints was enhanced by HBI‐8000, leading to a notable increase in tumor regression in the mice models. HBI‐8000 augmented the activity of ICIs antibodies targeting these immune checkpoints and significantly increased tumor regression in the mice models, which strongly supported the use of combination therapies involving ICIs and HBI‐8000 [ 132 ].

Recent investigations have demonstrated that the combination of ICIs with other immunotherapies is a major trend in the immunotherapy of hematological malignancies [ 133 , 134 ]. However, further investigations are necessary to explore and demonstrate the efficacy and safety of those combined therapies. In the future, researchers should explore more combination regimens based on ICIs, test the anti‐tumor effects of combinations in ex vivo experiments and explore the underlying molecular mechanisms. At the same time, a large number of preclinical and clinical studies should be performed to evaluate their efficacy and adverse effects and search for biomarkers to guide the selection of combination regimens so as to promote the clinical application of ICIs combination therapy in hematological malignancies.

BARRIERS TO THE APPLICATION OF IMMUNE CHECKPOINT INHIBITORS IN HEMATOLOGICAL MALIGNANCIES

Drug resistance of ICIs in hematological malignancies

Drug resistance, which is primarily associated with biological processes related to tumor immunity, is an important factor affecting the effectiveness of ICIs. The speculated mechanisms of resistance to ICIs can be broadly categorized into several groups, including inadequate tumor antigenicity, tumor‐intrinsic IFN‐γ signaling, loss of MHC, and disordered regulation of oncogenic signaling [ 135 ]. The mechanism of tumor resistance to ICIs is systematically illustrated in Figure 2 .

Firstly, following treatment with ICIs, loss of function mutations in Beta‐2‐microglobulin (B2M) could lead to MHC I loss and represent a molecular route of immune escape [ 136 ]. Recently, truncation changes in B2M have been repeatedly found in acquired resistance to ICIs [ 137 , 138 , 139 ]. The absence of MHC I and II expression may also be due to the loss‐of‐function mutations in Janus kinase (JAK) 1/2 and B2M genes. It has been reported that the expression of MHC molecules can be induced by several drugs, such as Toll‐like receptor agonists, histone deacetylase (HDAC) inhibitors, etc. [ 140 ]. Cellular therapies, such as CD40 agonists or CAR‐T, can also be effective in tumors with impaired expression of such MHC molecules [ 141 ].

Secondly, the essential initial process in the JAK‐STAT pathway, which triggered the apoptosis of tumor cells, was the activation of receptor‐associated kinases JAK1 and JAK2 binding to the IFN‐γ‐receptor 1/ receptor 2 (R1/R2) [ 15 ]. Several cases of inactivating mutations in JAK1 or JAK2 suggested that mutations in this pathway may lead to the progression of ICIs resistance [ 137 , 142 , 143 ]. A study in NK cell/T‐cell lymphoma found that the HDAC inhibitor chidamide, recently approved for the treatment of patients with r/r peripheral T‐cell lymphoma (PTCL), was associated with an ORR and CRR of 39% and 18%, respectively [ 144 ]. In‐vitro studies have shown that overactive JAK‐STAT signaling in NKTL cell lines is associated with resistance to chidamide [ 144 ]. Another study in cutaneous T‐cell lymphoma showed that n‐(4‐ethoxycarbophenyl) retinamide (ECPIRM), the 13‐cis retinoic acid derivative, inhibited the expression of the JAK/STAT pathway, thereby inhibiting cell proliferation and promoting apoptosis, which may also address the resistance to ICIs triggered by the JAK/STAT pathway [ 145 ]. Therefore, inhibition of JAK‐STAT activity could reprogram chromatin from a drug‐resistant to a sensitive state, overcome drug resistance to ICIs and produce synergistic anti‐tumor effects in vitro and in vivo.

Thirdly, the absence of the tumor suppressor phosphatase and tensin homolog ( PTEN ), which regulated phosphatidylinositol 3‐kinase (PI3K) activity, had also been observed in cases of acquired resistance to ICIs [ 146 , 147 , 148 ]. PTEN deficiency in lymphoid malignancies has been associated with advanced disease, chemotherapy resistance, and poor survival [ 149 ]. The combination of PI3K inhibitors and ICIs could be a potential strategy to improve the drug resistance to ICIs in hematological malignancies, but a large number of clinical trials are still needed to further validate the feasibility.

Lastly, several studies have reported the increased expression of other immune checkpoints at the time of acquired resistance, including TIM3 [ 150 ], VISTA [ 151 ], and LAG‐3 [ 139 ]. As mechanisms of resistance were inferred from circumstantial data in some reports, the exact mechanism of resistance to ICIs remains uncertain. One study included 19 AML patients treated with azacitidine and avelumab, and the findings demonstrated that PD‐L2 expression was increased during treatment in both BM and PB [ 152 ]. Therefore, high expression of PD‐L2 in BM may be an essential mechanism for the resistance to anti‐PD‐L1 therapy in AML patients [ 152 ]. In general, unremitting research on tumor resistance to ICIs will expand the spectrum of patients who can benefit from ICIs. Though the mechanism of ICIs resistance in hematological malignancies is still unclear, there are still feasible solutions, such as the combination of ICIs with chemotherapeutic agents, antiangiogenic agents, or radiotherapy. Combination application is the current research hotspot for resisting and reversing immune resistance, which still needs further clinical research. In view of the possible increased risk of toxicities, the combination of multiple ICIs requires careful assessments of benefits and risks before determining the treatment regimen.

Toxicity of ICIs in hematological malignancies

So far, an unavoidable problem with ICIs is irAEs [ 153 , 154 ]. The mechanisms of irAEs related to ICIs are complex and not fully comprehended but are currently known to be associated with aberrant T cell activity [ 133 , 155 ]. Shared antigens between tumor and normal tissue have been thought to activate nascent T cell response [ 133 ]. Nascent alterations in the peripheral B cell pool can also be used to explain the mechanisms of irAEs related to ICIs [ 156 ]. IrAEs related to ICIs can manifest in different human systems due to the disruption of the body's immune balance by ICIs [ 133 ]. IrAEs related to ICIs consist of dozens of different conditions that affect almost every organ system, including the skin, endocrine system, digestive system, etc. [ 157 , 158 ]. ICIs‐related irAEs of hematological malignancies are shown systematically in Figure 3 . IrAEs related to ICIs can be severe and even lethal in certain instances, especially in patients with underlying diseases [ 159 ].

Skin toxicity is the most common type of irAE related to ICIs in hematological malignancies, especially MM [ 160 ]. The usual and typical manifestations are maculopapular rash, pruritus, and exfoliative dermatitis [ 161 , 162 ], but rare skin necrosis [ 163 ] and Stevens‐Johnson syndrome [ 164 ] may also occur. Rash and pruritus occurred in 0%‐17% of patients receiving ipilimumab monotherapy and were mostly mild, usually defined as body surface area (BSA) grade 1‐2. Another PD‐1 inhibitor, pembrolizumab, can also cause skin toxicity [ 165 ]. Grade 1 (affecting <10% of BSA) and grade 2 (10%–30% BSA) skin irAEs are generally treated symptomatically and usually do not affect the continued use of ICIs. In a word, skin toxicity of hematological malignancies is diverse and variable in severity, with a high degree of individual variability. Skin toxicity is not as severe compared to other tissue toxicities, but it can have an impact on a patient's quality of life.

Endocrine organs, such as the thyroid, pituitary, adrenal, and pancreas, are frequently affected in patients who receive ICIs, leading to the development of irAEs [ 166 , 167 ]. Osteomalacia, thyroid dysfunction, insulin‐deficient diabetes mellitus, and primary adrenal insufficiency are among the reported ICIs‐related irAEs. Hypophysitis was associated with anti‐CTLA‐4 therapy [ 69 ], while thyroid dysfunction was associated with anti‐PD‐1 therapy [ 168 ]. Diabetes and adrenal insufficiency are comparatively rare but can be fatal if left untreated [ 167 ]. The use of ipilimumab, either alone or in combination with other therapies, was linked to the occurrence of thyroid dysfunction (0%‐6%) in cases of hematological malignancies such as CLL [ 162 ] and AML [ 70 ] after allo‐HSCT. There was a comparable occurrence of thyroid toxicity in cases where nivolumab and pembrolizumab were administered. Hypothyroidism was reported in 0%‐29% and 0%‐17% [ 169 ] of cases, respectively, while hyperthyroidism occurred in 0%‐13%[ 168 ] and 0%‐17% [170]of cases. Both of these two agents above also showed the occurrence of adrenal insufficiency with a maximum incidence of 6% [ 86 , 161 ]. Thyroid diseases generally do not require ICIs discontinuation. Cortisol levels should be tested to prevent adrenal crisis when TSH is decreasing [ 160 ]. Overall, endocrine toxicities are diverse, highly variable, and potentially fatal, requiring electrolyte and hormone examinations to detect this kind of irAEs.

Frequent occurrences of gastrointestinal (GI) irAEs to ICIs have been found particularly during anti‐CTLA‐4 therapy [ 166 , 171 ]. The clinical manifestations are diversified, including diarrhea, abdominal pain, hematuria, and even some extraintestinal manifestations. Meanwhile, upper gastrointestinal symptoms such as nausea and vomiting are less common [ 153 , 171 ]. Mild colitis is usually treated symptomatically with fluid and electrolyte repletion [ 153 ]. If symptoms get worse, ICIs need to be stopped immediately, and steroids should be given orally or intravenously as appropriate [ 172 ].

In general, pulmonary symptoms were more noticeable with anti‐PD‐1 or anti‐PD‐L1 monoclonal antibodies than with anti‐CTLA‐4 inhibitors. Pulmonary toxicity in ICIs is uncommon, but when present, it has the potential to worsen rapidly or even be fatal [ 166 ]. Pneumonia is one of the most common causes of ICIs discontinuation and is the primary cause of treatment‐related mortality in hematological malignancies. Clinical symptoms include dyspnea, cough, and chest pain, usually appearing about 10‐12 weeks after ICIs treatment [ 160 ]. The incidence of pulmonary toxicity for ipilimumab monotherapy was 0%‐11%. Nivolumab and pembrolizumab caused pneumonitis or upper respiratory tract infection in 0%‐24% [ 69 ] and 0%‐13% [ 161 ] of patients.

Cardiotoxicity in hematological malignancies occurs occasionally. The incidence rate of myocarditis was predicted to be 1.14%, with a median time to onset of 34 days [ 173 ]. Cases of myocarditis were observed in hematological malignancy patients such as r/r MM receiving ICIs therapy, and two cases were fatal and were caused by the combination of pembrolizumab and dexamethasone [ 174 , 175 , 176 ]. Pericarditis with pericardial pain, myocarditis with difficulty breathing caused by fluid accumulation in the lungs or arrhythmias with heart palpitations and fainting may indicate cardiotoxicity [ 177 , 178 ]. Therefore, the incidence of cardiac irAEs is low, but the mortality rate is high [ 179 ]. European Society for Medical Oncology (ESMO) Clinical Practice Guidelines recommend electrocardiography and troponin for all individuals [ 153 ]. When myocarditis is confirmed, it is necessary to discontinue ICIs and administer high‐dose corticosteroids to patients [ 172 ].

Other rare irAEs to hematological malignancies include nephrotoxicity and rheumatologic toxicity [ 180 , 181 ]. Arthralgia and myalgia are the most commonly reported rheumatic irAEs, while arthritis, myositis and vasculitis were also observed in trials of hematological malignancies treated with ICIs, such as CLL [ 90 ], r/r HL [ 182 ], AML [ 90 ], MDS [ 90 ], CML [ 90 ], r/r primary mediastinal B‐cell lymphoma [ 183 ], r/r peripheral T cell lymphoma [ 180 ]. These adverse events are more likely to occur in anti‐PD‐1 ICIs and may occur later than other irAEs [ 166 ]. The most common manifestation of nephrotoxicity is acute kidney injury (AKI) due to acute tubulointerstitial nephritis [ 166 , 181 ].

In general, irAEs to hematological malignancies can occur in all systems, among which cardiotoxicity and pulmonary toxicity, as well as endocrine toxicity, are more dangerous and require close monitoring of patients. The current strategy for dealing with irAEs is based on timely monitoring, early detection, and effective intervention [ 133 ]. While searching for alternatives to high‐dose corticosteroids to develop unique strategies for the treatment of irAEs [ 155 , 184 ], more scientific prevention and monitoring measures are also necessary. So, is it necessary to resume the use of ICIs after control of irAEs? There is still controversy over this question. The general recommendation is based on the grade determination of irAEs. For patients with grade 2 irAEs, ICIs can be reintroduced after the adverse effects have resolved to grade 1, and for grade 3 irAEs, it is generally recommended that ICIs should be discontinued. Importantly, restarting ICIs after the interruption of ICIs due to irAEs should be done in consultation with a specialist physician. If severe or life‐threatening irAEs have occurred, treatment with these ICIs must be permanently discontinued, and restarting ICIs should be done by choosing a different type of ICIs as much as possible. Besides, restarting ICIs should be done by monitoring the recurrence of previous irAEs and considering permanently discontinuing the treatment with these ICIs if irAEs are present again. It is more important to individualize the decision based on patient outcomes and whether irAEs are controlled.

PERSPECTIVES AND CONCLUSIONS

Immune checkpoints have been studied for almost four decades and still remain a hot topic in tumor treatment. Currently, the inhibitors of PD‐1 and CTLA‐4 have been widely used in HL [ 83 , 89 , 185 ] with favorable efficacy, which has been achieved in other lymphoma subgroups, such as r/r B‐NHL [ 69 ], primary mediastinal large B‐cell lymphoma [ 165 ] and NK/T‐cell lymphoma [ 186 ]. Immune checkpoints like PD‐1 have been identified to serve as potential biomarkers for hematological malignancies, and a large number of studies have been performed to explore the potential of targeting these immune checkpoints for the treatment of hematologic malignancies. [ 11 , 12 , 60 ]. In recent years, the emergence of novel immunotherapies, such as double antibiotics [ 118 , 119 ] and lysosomal viruses [ 111 ], has brought many new ideas for the application of ICIs. Moreover, there have been numerous attempts to address the issue of drug resistance to ICIs, and most researchers have taken the approach of combining ICIs with drugs that target specific pathways of resistance mechanisms, such as HDAC inhibitors that induce the expression of MHC molecules [ 144 ]. It is now generally accepted that close monitoring and appropriate intervention while using ICIs can mitigate irAEs. For example, according to recommendations of ESMO Clinical Practice Guidelines, it is advisable to administer concurrent broad‐spectrum antibiotics and immune suppression to mitigate pulmonary toxicity [ 153 ].

In conclusion, since the efficacy of ICIs therapy in hematological malignancies varies considerably, it is necessary to explore the potential of immune checkpoints as biomarkers to decide whether to use ICIs, as well as to predict their therapeutic responses. The underlying mechanism of immune checkpoints is yet to be dug deeper, and new immune checkpoints are urgently needed to be discovered and applied to provide biomarkers and molecular targets for tumor treatment. Although new ICIs are undergoing a large number of clinical trials, whether already approved ICIs can be used in combination and the effect of the combination are still the factors that most directly affect the outcome of patients with hematological malignancies. At the same time, we cannot ignore the fact that a significant proportion of patients with hematological malignancies do not respond to ICIs therapies. However, due to the unclear mechanism of drug resistance and the lack of validation trials with large sample sizes, the strategy of combining drugs to combat resistance to ICIs remains to be validated and explored in hematological malignancies. In addition, facing irAEs, how to avoid or minimize the harm of side effects is also the most concerned part of researchers. We believe that persistent research on ICIs will increase their effectiveness, mitigate adverse effects, and ultimately expand the percentage of patients who can benefit from ICIs.

AUTHOR CONTRIBUTIONS

Wenyue Sun wrote this manuscript and created figures and tables. Xin Wang and Shunfeng Hu revised the manuscript. Xin Wang provided guidance throughout the preparation of the manuscript. All authors read and approved the final manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no competing interests.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Not applicable.

CONSENT FOR PUBLICATION

Not applicable.

ACKNOWLEDGMENTS

This study was funded by the National Natural Science Foundation (No.82270200, No.82070203 and No.81770210); Key Research and Development Program of Shandong Province (No.2018CXGC1213); Taishan Scholars Program of Shandong Province (No.tspd20230610, NO.tsqnz20231251); Translational Research Grant of NCRCH (No.2021WWB02, No.2020ZKMB01); Shandong Provincial Engineering Research Center of Lymphoma; Academic Promotion Programme of Shandong First Medical University (No. 2019QL018); China Postdoctoral Science Foundation (No. 2023M741506); Shandong Provincial Natural Science Foundation (No. ZR2023QH193).

DATA AVAILABILITY STATEMENT

Not applicable.

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