TIGIT in cancer immunotherapy

Abstract

Tumors evade immune-mediated recognition through multiple mechanisms of immune escape. On chronic tumor antigen exposure, T cells become dysfunctional/exhausted and upregulate various checkpoint inhibitory receptors (IRs) that limit T cells' survival and function. During the last decade, immunotherapies targeting IRs such as programmed cell death receptor 1 (PD-1) and anticytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have provided ample evidence of clinical benefits in many solid tumors. Beyond CTLA-4 and PD-1, multiple other IRs are also targeted with immune checkpoint blockade in the clinic. Specifically, T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is a promising new target for cancer immunotherapy. TIGIT is upregulated by immune cells, including activated T cells, natural killer cells, and regulatory T cells. TIGIT binds to two ligands, CD155 (PVR) and CD112 (PVRL2, nectin-2), that are expressed by tumor cells and antigen-presenting cells in the tumor microenvironment. There is now ample evidence that the TIGIT pathway regulates T cell-mediated and natural killer cell-mediated tumor recognition in vivo and in vitro. Dual PD-1/TIGIT blockade potently increases tumor antigen-specific CD8⁺ T cell expansion and function in vitro and promotes tumor rejection in mouse tumor models. These findings support development of ongoing clinical trials with dual PD-1/TIGIT blockade in patients with cancer.

Keywords: costimulatory and inhibitory T-cell receptors; immunotherapy; investigational; therapies.

Figure 1

The TIGIT/CD226/CD96/CD112R axis. TIGIT, CD226, CD96, and CD112R are expressed on activated T cells and NK cells. TIGIT ligands CD115 and CD112 are expressed on APCs or tumor cells. TIGIT binds CD155 and CD112 as well as Fap2, a gut bacterium-derived protein. TIGIT, CD96, CD112R, and CD155 contain ITIM motifs in their cytoplasmic tail that trigger inhibitory signals. TIGIT also contains an ITT-like motif. CD226 associates with LFA-1 and binds CD155 to deliver a positive signal. CD96 binds CD155, and whether this triggers inhibitory or activating signals in human T cells remain to be determined. CD112R binds CD112 to deliver an inhibitory signal through its ITIM. APCs, antigen-presenting cells; ITIM, immunoreceptor tyrosine-based inhibitory motif; ITT, Ig tail-tyrosine; NK cells, natural killer cells; TIGIT, T cell immunoreceptor with immunoglobulin and ITIM domain.

Figure 2

Mechanisms of TIGIT inhibition of T cells in the TME. TIGIT displays multiple inhibitory mechanisms in T cells. 1: TIGIT binds CD155 and triggers direct inhibitory signals in T cells. 2: TIGIT binds CD155 on APCs to trigger IL-10 production and decrease IL-12 production, which indirectly inhibits T cells. 3: TIGIT binds CD155 with higher affinity than CD226 or disrupts CD226 homodimerization to impede CD226-mediated T cell activation. 4: TIGIT signaling in Tregs enhances their immunosuppressive functions. 5: Fap2 protein from the gut bacteria Fusobacterium nucleatum binds TIGIT to trigger inhibitory signals. APCs, antigen-presenting cells; IL, interleukin; ITIM, immunoreceptor tyrosine-based inhibitory motif; TIGIT, T cell immunoreceptor with immunoglobulin and ITIM domain; Tregs, regulatory T cells.