TIGIT, the Next Step Towards Successful Combination Immune Checkpoint Therapy in Cancer

Abstract

T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory receptor expressed on several types of lymphocytes. Efficacy of antibody blockade of TIGIT in cancer immunotherapy is currently widely being investigated in both pre-clinical and clinical studies. In multiple cancers TIGIT is expressed on tumor-infiltrating cytotoxic T cells, helper T cells, regulatory T cells and NK cells, and its main ligand CD155 is expressed on tumor-infiltrating myeloid cells and upregulated on cancer cells, which contributes to local suppression of immune-surveillance. While single TIGIT blockade has limited anti-tumor efficacy, pre-clinical studies indicate that co-blockade of TIGIT and PD-1/PD-L1 pathway leads to tumor rejection, notably even in anti-PD-1 resistant tumor models. Among inhibitory immune checkpoint molecules, a unique property of TIGIT blockade is that it enhances not only anti-tumor effector T-cell responses, but also NK-cell responses, and reduces the suppressive capacity of regulatory T cells. Numerous clinical trials on TIGIT-blockade in cancer have recently been initiated, predominantly combination treatments. The first interim results show promise for combined TIGIT and PD-L1 co-blockade in solid cancer patients. In this review, we summarize the current knowledge and identify the gaps in our current understanding of TIGIT's roles in cancer immunity, and provide, based on these insights, recommendations for its positioning in cancer immunotherapy.

Keywords: CD155; CD226; NK cells; T cells; immunotherapy.

Figure 1

Mechanisms of TIGIT inhibition in T cells. TIGIT displays multiple inhibitory mechanisms in T cells. 1) TIGIT binds to CD155 and delivers intracellular inhibitory signals which directly reduces TCR-expression and TCR signaling. 2) TIGIT binds to CD155 with much higher affinity than its co-stimulatory counterpart CD226 and thereby can replace CD226 from CD155 binding; 3) or disrupts CD226 homo-dimerization to inhibit CD226-mediated T cell activation. 4) TIGIT binds to CD155 on APCs to induce IL-10 production and decrease IL-12 production which indirectly inhibits T cells. APCs, antigen-presenting cells. The figure is adapted based upon the cartoon from Pauken KE et al. (53).

Figure 2

Dual blockade of TIGIT and PD-1 has synergistic effects on intra-tumoral CD8+ T cells. (A) CD226 co-stimulatory signaling is suppressed by both TIGIT and PD-1 signaling. (B) Co-blockade of PD-1 and TIGIT synergizes to restore CD226 co-stimulatory signaling.

Figure 3

Ligation of TIGIT on Tregs contributes to dampening of anti-tumor immunity. (A) Ligation of TIGIT augments suppressive function of Tregs, which inhibits Th1/17 cell, CD8⁺ T cell or NK responses via production of Fgl2 and IL-10. On the contrary, PD-1 ligation may reduce Treg suppressive function. (B) Single blockade of PD-1 may enhance Treg immunosuppression, whereas dual blockade of TIGIT and PD-1 may counteract this resistance mechanism.

Figure 4

Blockade of TIGIT on NK cells augments anti-tumor immunity. (A) NK cells expressing TIGIT are functionally impaired by binding to CD155 and nectin-4, and in colorectal cancer to Fap2 protein produced by a gut bacterium. (B) TIGIT blockade not only interrupts inhibitory signaling by TIGIT in NK cells, but also allows interaction of the co-stimulatory receptor CD226 with CD155. IL-15 treatment increases TIGIT and CD226 expression on NK cells. Thus IL-15 combined with TIGIT blockade further enhanced NK cells anti-tumor functions, especially promoting NK cell-mediated destruction of MHC class I-deficient tumors.