TIGIT/PVR axis regulates anti-tumor immunity in hematologic malignancies.

Introduction

Immune checkpoint inhibitors (ICIs) T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), programmed cell death protein-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) have become approved for clinical use in several solid tumors and hematological malignancies [ 1 , 2 ]. ICI has proven to be effective for hematologic malignancies. Blocking immune checkpoints PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT have been reported with significant success in acute myeloid leukemia (AML) [ 3 – 7 ], lymphoma [ 8 , 9 ], myelodysplastic syndromes (MDS) [ 10 , 11 ], and multiple myeloma (MM) [ 12 – 14 ]. TIGIT, an inhibitory receptor that interacts with poliovirus receptor (PVR, CD155) and (PVRL2, CD112), is considered as a checkpoint in T and NK cell activation that is widely expressed on both T and NK cells [ 12 , 15 – 17 ]. Interestingly, TIGIT competes with the costimulatory receptor CD226, binding to the same receptors, PVR and CD122, but having the opposite effect [ 18 ]. TIGIT has a stronger affinity to PVR than CD226, and the binding of TIGIT to PVR inhibits the binding of CD226 to PVR [ 19 ]. Patients with hematologic malignancies expressed high levels of TIGIT was associated with poor survival, fast progression and early fatality. Considering the limitations of existing treatments, targeting TIGIT may become a useful therapy. Targeting TIGIT shows great potential for therapeutic potential in AML, MDS, MM and lymphoma [ 3 , 12 , 20 , 21 ]. One result suggested that Treg/CD8 + T cells expressing TIGIT favor B-ALL progression, and targeted TIGIT could be a promising approach for B-ALL [ 22 ]. Herein, we summarize the current knowledge regarding the mechanisms of TIGIT and discuss the results of recent trials that used anti-TIGIT antibodies in hematologic malignancies.

The current therapeutic landscape in hematologic malignancies

Hematologic malignancies include lymphoproliferative and myeloproliferative disorders, mainly AML, chronic lymphocytic leukemia (CLL), MDS, MM and lymphoma [ 23 ]. AML is the most common type of myeloid malignancy characterized by a reduction of normal hematopoiesis and proliferation of leukemic blasts in the blood and bone marrow [ 24 ]. Hematologic malignancies mainly occur in elderly patients with unfavorable prognosis, limited treatment options and management difficulties, the median age in AML [ 25 ], MDS [ 26 ] and MM [ 27 ] over 60 years, except lymphoma. Even with new treatments, most hematological malignancies are still incurable diseases, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still the cure of choice. However, only a minority of patients are eligible for the only potentially curative therapy due to age, donor availability, infections, disease characteristics, graft-versus-host disease (GVHD), regimen-related toxicities, and graft rejection. In addition, relapse after HSCT can still occur [ 28 ]. Despite better understanding of the molecular pathogenesis and advances in treatment options, new treatments are urgently needed to improve the survival of patients with hematologic malignancies.

Hematologic malignancies remains an incurable disease with high relapse rate, poor prognosis and short survival time even with new treatment strategies [ 29 ]. Chemotherapy, supportive care, proteasome inhibitors, hypomethylating agents (HMAs) and monoclonal antibodies, but HSCT remains as the only potentially curative therapy [ 30 ]. However, HSCT is associated with a significant risk of transplant-related mortality and other limitations, contributing to a challenge in many cases, new and effective treatments are needed [ 31 ]. The major novel therapeutic strategies in hematologic malignancies include targeting innate and inflammatory signaling (NLRP3, IL-1b, MDSC elimination and TLR signaling), specific somatic mutations (TP53, FLT3, IDH1, IDH2, JAK2, SF3B1 [ 32 ], WT1 and TET2), chimeric antigen receptor (CAR) therapy (CAR-T or CAR-NK) and novel ICIs (PD-1, TIGIT, TIM-3, CTLA-4 and LAG-3) [ 30 , 33 – 38 ]. All these are outlined in Fig. 1 . In view of the great therapeutic potential of targeted TIGIT in hematological tumors, we will focus on its role in hematological tumors [ 39 ].

Structure and expression of TIGIT

TIGIT, also known as WUCAM, Vstm3, and VSIG9, is a co-inhibitory receptor belonging to a constantly expanding family of PVR like proteins. TIGIT is composed of an extracellular immunoglobulin (Ig) variable domain, a type I transmembrane domain, and an intracellular domain containing an ITIM and an Ig tail-tyrosine (ITT)-like motif [ 40 ].TIGIT is identified as an immune checkpoint that is expressed in lymphocytes (NK cells and T cells, including CD4 + T cells, CD8 + T cells and Tregs) and plays a key role in immunoregulation [ 16 ].

The PVR–TIGIT axis in the regulation of the immune response

PVR (CD155), a high affinity receptor to TIGIT, is over expressed on dendritic cells (DCs) and tumor cells [ 41 ]. TIGIT has three ligands, PVR, CD112 and CD113, but the main ligand for TIGIT is PVR [ 16 , 42 ]. TIGIT and DNAM-1(CD226) bind to PVR, but with different affinity and function. Inhibitory receptor (TIGIT) with higher affinity and activating receptor (CD226) with lower affinity compete for the same PVR ligands in regulating T cell and NK cell function [ 43 , 44 ]. TIGIT is an important inhibitory receptor in the PVR/CD155 family. PVR and TIGIT co-recruit SHIP-1, block PIK-3, NF-kB or MAPK signaling pathways, and inhibit NK and T-cell-mediated cytotoxicity [ 45 , 46 ], and is also associated with NK and T cell exhaustion [ 47 ]. T cell exhaustion indicates that T cells are in a state of functional inhibition, resulting in decreased ability to kill tumors, which can lead to tumor progression [ 48 ]. TIGIT via interaction with PVR effectively interrupts the communication of the PVR with CD226 and CD96 [ 49 ]. Of note, CD96 contains an inhibitory intracellular ITIM domain(like TIGIT)and an YXXM motif(activating receptor), involved in immune function through either activation or inhibition in response to different cells, but the exact mechanism remains to be elucidated [ 16 ]. The correlation between anti-tumor effect and PVR–TIGIT axis are illustrated in Fig. 2 . NK and T cells are the main effector cells that play an anti-tumor role. Targeted TIGIT can be used in the treatment of many kinds of tumors.

The role of TIGIT-PVR in cancer

Previous studies indicated that over-expression TIGIT and PVR promotes tumor cell invasion and migration, and is associated with tumor progression and poor prognosis for many cancers [ 50 ]. Relative plasma concentrations of PVR proteins in blood from patients having different types of cancer measured by proximity extension assay (PEA). PEA results showed that PVR expression was upregulated in AML, glioma, and large B-cell lymphoma (Fig. 3 A). As we all know, gene mutation is closely related to the occurrence of tumor. A Pan-cancer genomic analysis of whole genome indicated that mainly mutations in TIGIT were R121I, A148T, L150P and P197S, in PVR were V18E, M75I, V135M, S181L, E324K and E386Q (Fig. 3 B). Genetic changes were missense mutation, amplification and deep deletion, which were found in 4% and 5% of TIGIT and PVR respectively (Fig. 4 A). The most common alterations in the TIGIT and PVR were gene amplifications and deep deletions (Fig. 4 B). Survival data show that TIGIT and PVR gene mutations reduce the overall survival rate of patients (Fig. 4 C). These results need further confirmation.

The role of TIGIT-PVR in hematologic malignancies

In view of the role of TIGIT and PVR in tumors, we further analyzed their role in hematological tumors. Data from the Microarray Innovations in Leukemia study (MILE) ( https://servers.binf.ku.dk/bloodspot/ ) demonstrated that TIGIT and PVR are highly expressed in hematologic malignancies (Fig. 5 A) [ 51 – 53 ]. PVR was highly expressed in AML and CLL, especially AML with t (15;17) and t (8;21), while TIGIT was especially prevalent in CLL compared to other leukemias (Fig. 5 B). All of these studies strongly suggest that targeting TIGIT is a novel and effective treatment for hematologic malignancies.

The expression levels of TIGIT, CD226 and PVR in normal hematopoietic cells

In order to study the expression levels of TIGIT, CD226 and PVR in normal hematopoietic cells, the expression data showed that TIGIT and CD226 had similar distribution patterns and were more strongly expressed in NK and CD8 + T cells (Fig. 6 A-B). However, PVR was highly expressed in polymorphonuclear cells from peripheral blood (PMN-PB) (Fig. 6 C). The 3D structure of TIGIT was obtained using the cBioportal tool. (Fig. 6 D). Blood cell type expression from RNA-seq data shows TIGIT higher expressed in T-reg (regulatory T cells), CD226 higher expressed in GdT(gamma-delta) cell and NK-cell, PVR higher expressed in Monocytes (Fig. 6 E-F). Data obtained from Human protein mapping database ( https://www.proteinatlas.org/ ) of HPA (Human protein atlas) RNA - seq.

Target TIGIT for the treatment of hematologic malignancies

The PVR–TIGIT axis in AML and MDS

Recent studies have shown that AML and MDS by over-expression of ICIs (TIGIT, TIM-3 and PD-1) and their ligands to deviate host immune responses resulting tumor progression [ 54 ]. Due to the encouraging clinical efficacy of PD-1 in solid tumors, most of the studies in hematologic malignancies are targeted to PD-1, but there are limited studies on targeting TIGIT. Moreover, TIGIT may play an important role in treatment of AML and MDS. Valhondo et al. showed that AML patients had a significant decrease in the percentage of CD226 and an increase in the percentage of TIGIT on T and NK cells, which was also associated with patient survival [ 55 ]. Myeloid-derived suppressor cells (MDSCs) inhibit NK cells in MDS through the TIGIT/PVR pathway, and after blocking TIGIT-PVR pathway, NK cell function was reversed [ 56 ]. Our previous study demonstrated that the overexpression of TIGIT inhibited the activity of NK and T cells in patients with MDS, blocking TIGIT and PD-1 was observed to be more effective in improving T and NK cell functions and anti-tumor immunity [ 57 ]. AML with FMS-like tyrosine kinase 3 (FLT3) mutation has poor response to treatment and worse prognosis [ 58 ]. It has been found that PVR and CD112 can activate Raf-MEK-ERK signaling pathway, which is also the signaling pathway of FLT3, indicated that PVR and CD112 as possible targets of immunotherapy for AML with FLT3 mutation [ 59 ]. To date, there are currently no human clinical trials for treatment of AML or MDS with TIGIT inhibitors. Therefore, the target TIGIT axis in AML and MDS requires further investigation.

The PVR–TIGIT axis in MM

MM is an incurable plasma cell hematologic malignancy mainly in the elderly and is the second most common hematologic malignancy [ 60 ]. ICIs, proteasome inhibitors, monoclonal antibodies, CAR-T cells and bi-specific antibodies have benefited patients with MM, but effective treatments are still lacking [ 61 ]. Targeting NK cell inhibitory receptors (TIGIT, PD-1 and TIM-3) is a potential strategy method for MM [ 62 ]. PVR is highly expressed in patients with MM, PVR expression is related with MM stage and poor prognosis, and is a potential prognostic indicator for MM [ 63 ]. MM patient TIGIT + CD8 + T cells also exhibited decreased CD107a, TNF-α, and IFN-γ expression, reduced proliferative capacity, indicating poor killing capability. Anti-TIGIT mAbs treatment significantly improved CD8 + T cell depletion in MM tumor cells [ 12 ]. However, mechanism of action of the TIGIT in MM is still unclear. Nuclear factor-κB (NF-κB) transcription factors play a key role in the survival, proliferation and chemoresistance of mesenchymal stromal cells (MSCs) from MM [ 60 , 64 , 65 ]. B cell receptor (BCR), toll-like receptor 4 (TLR 4) and cytokines TNF-α and IL-1 β receptor can activate typical NF-κ B signal transduction. Activation of NF-κB signaling pathway leads to higher expression of PVR, which may be the mechanism of its action and needs to be verified. At present, the clinical trials of targeting TIGIT to treat MM are still in progress, and there is no result yet ( NCT04150965 , NCT05289492 ).

The PVR–TIGIT axis in lymphoma

Lymphoma can be roughly divided into Non‑Hodgkin’s lymphoma (NHL) and Hodgkin’s lymphoma (HL) [ 66 ]. T cells from NHL tumors displayed high expression of TIGIT and PD-1, and expression of TIGIT in T cells correlated with suppression of IFN-γ, TNF-α and IL-2 cytokine production [ 9 ]. Overexpression of TIGIT and PD-1 in T lymphocytes of cHL patients, and TIGIT is a target for immunotherapies in cHL [ 67 ]. CAR-T is a new effective method for the treatment of lymphoma, but it still recurs after treatment. Vivian Changying Jiang reported that TIGIT is the central player in T-cell suppression associated with CAR T-cell relapse, and co-targeting TIGIT may prevent CAR T relapses in mantle cell lymphoma (MCL) [ 68 ]. Single-cell RNA and protein expression data indicates that TIGIT as a marker of CD19 CAR-T Cell Dysfunction in Patients with NHL, and TIGIT blockade improves the antitumor function of CAR-T cells [ 69 ]. Clinical trials of targeted TIGIT for lymphoma are ongoing ( NCT05315713 , NCT04818619 , NCT04045028 ).

The PVR–TIGIT axis in CLL and ALL

Over-expression of TIGIT in CD4 + T cells provide a supportive microenvironment for CLL cells, representing a potential therapeutic target for CLL treatment [ 70 ].However, Hatefi F reported that combined blockade of PD-1 and TIGIT had no effect on restoring the function of CD8 + T-cells from the peripheral blood in CLL [ 71 ]. One reason maybe TIGIT is highly expressed on CD4 and CD8 + T in patients with CLL, and negatively correlated with BCR signaling pathway activity, which indicates that CLL is a more indolent disease [ 72 ]. The combination of TIGIT and ibrutinib can improve this situation, suggesting that other mechanisms of T depletion in CLL patients may exist. At present, there is very little research on TIGIT in ALL, and only 7 literatures are searched by using TIGIT and ALL as Title/Abstract. Ukrainskaya VM isolated extracellular vesicles (EVs) from B cell precursor leukemia cell line (pre-B ALL) Nalm-6 and demonstrated that chronic exposure of CD19-CAR T cells to CD19+ (EVs) upregulated the TIGIT expression [ 73 ].However, one research indicated that knock-out of TIGIT in NK-92 and CD276-CAR-NK-92 did not significantly enhanced cytotoxicity against AML and ALL cell lines [ 74 ]. RNA-sequencing of T-cells isolated from vehicle and rIL-12 treated mice with B-ALL revealed that the leukemia-induced increase in LAG-3, TIGIT, and IL-10 genes [ 75 ]. Overexpression of LAG3, PD-1, TIGIT and HAVCR2 was observed in CD4-exhaustion and CD8-exhaustion T cells in B-ALL patients [ 76 ]. Blinatumomab is a dual targeted CD3 and CD19 specific antibody used for the treatment of ALL. T cell exhaustion increased expression of PD-1, Tim-3, and TIGIT could be the possible mechanism of refractoriness to blinatumomab in B-ALL [ 77 ]. TIGIT expression is upregulated in T cells and causes T cell dysfunction independent of PD-1 and Tim-3 in adult B-ALL [ 78 ].These studies indicate that T cell depletion leads to the existence of immunosuppressive microenvironment in ALL, which is related to the high expression of TIGIT and PVR. Targeting TIGIT-PVR may be a new treatment method, and the exact mechanism in ALL needs further study.

Clinical trials targeting the PVR–TIGIT axis in hematologic malignancies

Due to the absence of effective therapeutic options, patients afflicted with hematologic malignancies face grim prognoses. The predominant treatment modality for most hematologic malignancies remains chemotherapy, with HSCT serving as a curative option. Despite numerous investigations into ICIs such as PD-1, PD-L1, TIM-3, LAG-4, and TIGIT, some of which have yielded favorable clinical outcomes, TIGIT-targeted therapies have yet to receive approval for hematologic malignancies. Notably, the CITYSCAPE trial, registered with ClinicalTrials.gov under NCT03563716 , is a phase 2 study characterized by randomization, double-blinding, and placebo control. It assesses Tiragolumab, an anti-TIGIT antibody, in combination with atezolizumab (a PD-L1 blocker) in chemotherapy-naive patients diagnosed with locally advanced or metastatic non-small cell lung cancer (NSCLC). The results of this trial indicated that the combination therapy of tiragolumab and atezolizumab was well-tolerated and demonstrated clinically significant enhancements in various parameters, including objective response rate (31.3% [95% CI 19.5–43.2] vs. 16.2% [6.7–25.7], p = 0.031), progression-free survival (5.4 months vs. 3.6 months, hazard ratio 0.57 [95% CI 0.37–0.90], p = 0.015), and overall survival (23.2 months vs. 14.5 months, HR 0.69 [95% CI 0.44–1.07], p = 0.093) within the intention-to-treat population when compared to atezolizumab monotherapy [ 79 ]. Currently, TIGIT-targeted therapy for hematological malignancies remains in the clinical trial phase (Table 1 ). Multiple clinical trials are underway, focusing on TIGIT inhibition either as a standalone therapy or in combination with anti-PD-1/PD-L1 antibodies or chemotherapy for the treatment of malignant lymphoma, CLL, and MM. These trials have yet to yield conclusive results, and we eagerly await the outcomes of TIGIT-targeted therapies in hematological malignancies.

Conclusion

Blocking TIGIT and reversing the immunosuppressive microenvironment is a promising approach for hematological tumors. Combined chemotherapy or other ICIs such as PD-1/PD-L1 can further improve the curative effect. The treatment of malignant hematological diseases is extremely challenging and the basic research of TIGIT-PVR signaling pathway shows great therapeutic potential, but the effectiveness and safety of targeted TIGIT in the treatment of hematological tumors still need to be further confirmed by clinical trials. In addition, given the complex pathogenesis and tumor microenvironment of hematological malignancies, the targeted therapy for TIGIT still needs further research to develop more effective therapies.

Author contributions

Fanqiao Meng designed the study, analyzed and interpreted data, and wrote the manuscript. Maoyuan Xiang and Yu Liu assisted with data interpretation, and edited the manuscript. Dongfeng Zeng provided valuable guidance and revised the paper. All authors read and approved the final manuscript.

Funding

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethical approval

This article does not contain any studies with animals/human participants performed by any of the authors.

Research involving human participants and/or animals

No.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.