TIGIT: A promising target to overcome the barrier of immunotherapy in hematological malignancies

Abstract

Immune evasion through up-regulating checkpoint inhibitory receptors on T cells plays an essential role in tumor initiation and progression. Therefore, immunotherapy, including immune checkpoint inhibitor targeting programmed cell death protein 1 (PD-1) and chimeric antigen receptor T cell (CAR-T) therapy, has become a promising strategy for hematological malignancies. T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is a novel checkpoint inhibitory receptor expressed on immune cells, including cytotoxic T cells, regulatory T cells, and NK cells. TIGIT participates in immune regulation via binding to its ligand CD155. Blockage of TIGIT has provided evidence of considerable efficacy in solid tumors in preclinical research and clinical trials, especially when combined with PD-1 inhibition. However, the mechanism and function of TIGIT in hematological malignancies have not been comprehensively studied. In this review, we focus on the role of TIGIT in hematological malignancies and discuss therapeutic strategies targeting TIGIT, which may provide a promising immunotherapy target for hematological malignancies.

Keywords: TIGIT; hematological malignancy; immunotherapy; leukemia; lymphoma; multiple myeloma.

Figure 1

The interaction of TIGIT family receptors and ligands. TIGIT, CD226, CD96 and CD112R are expressed on T cells and NK cells. The ligands CD155, CD113, CD112 and PVRL4 are expressed on tumor cells or APCs. TIGIT delivers inhibitory signals by binding to CD155, CD113, CD112 and PVRL4, with highest affinity for CD155. CD226 and CD96 compete with TIGIT for binding to CD155, but with lower affinity than TIGIT. CD226 delivers activating signals. However, whether CD96 triggers inhibitory or activating signals remains to be determined. CD112R and CD226 also competitively binding to CD112, with higher affinity with CD112R. APCs, antigen presenting cells.

Figure 2

Mechanism of inhibitory role of TIGIT in immunoregulation. (1) Interaction of TIGIT with CD155 transmits intracellular inhibitory signals, which directly suppressed TCR signal and effector T cell function. (2) TIGIT inhibits CD226-induced T cell activation by disrupting CD226 homodimerization and decreasing IFNγ production. (3) TIGIT directly induces NK cell exhaustion, contributing to inactivation of CD8+ T cell. (4) TIGIT enhances Tregs mediated dysfunction of effector T cell by increased IL-10 and Fgl2, as well as inhibition of Th1 and Th17 cells. (5) TIGIT promotes macrophage switching from pro-inflammatory M1 to anti-inflammatory M2 phenotype through increased IL-10 and decreased IFNγ and TNFα. (6) TIGIT inhibits T cell function by DCs-mediated abnormal secretion of cytokines. IFNγ, interferon-γ; IL-10, interleukin-10; Fgl2, fibrinogen-like protein 2; Th1, T helper 1 cell; Th17, T helper 17 cell; TNFα, tumor necrosis factor α; DCs, dendritic cells; NK, natural killer.