T-cell immunoglobulin and ITIM domain as a target in combo anti-PD-(L)1 cancer therapy.

Immunoregulatory roles of T-cell immunoglobulin and ITIM domain (TIGIT) in solid tumors, and its interactions with other checkpoints is a focus of research in cancer immunotherapy. The increased activity of TIGIT/CD155 promotes dendritic cell (DC) tolerance and CD8+ T cell exclusion/energy/exhaustion. Increased TIGIT activity also hampers natural killer (NK) cell function and increases immunosuppressive activity of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), with the latter serving as a key cell type to pursue TIGIT regulatory effects in tumor immune ecosystem. Frequent co-expression of TIGIT with programmed death-1 (PD-1) on CD8+ T cells along with the increased TIGIT expression in Tregs after anti-PD-1 therapy, the stimulatory effect of TIGIT+ Tregs on T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and the inducible effect of anti-programmed death-ligand 1 (PD-L1) on CD155 are all rationalizing a possibility for application of anti-TIGIT as a desired combinatory with anti-PD-(L)1 drugs in cancer immunotherapy. TIGIT can also be a target for development of bispecific antibodies to simultaneously target activities within the TIGIT/CD155 and PD-1/PD-L1 axes or for dual targeting of two inhibitory receptors, such as TIGIT/anti-poliovirus receptor-related immunoglobulin domain-containing protein (PVRIG), with the latter also acting to hamper activation of other inhibitory receptors occurring secondary to the anti-TIGIT therapy.