TIGIT in cancer: from mechanism of action to promising immunotherapeutic strategies

Abstract

TIGIT immune checkpoint (IC) has attracted great interest in recent years. It belongs to the PVR-like protein family, and it inhibits T and NK cell cytotoxic activities. TIGIT mediates its inhibitory effect by direct signaling through the cytoplasmic tail, CD155-mediated inhibition, or competition with the immune-activating receptor CD226. Preclinical observations from studies involving TIGIT-specific blocking monoclonal antibodies (mAbs) are promising, but the results of the clinical trials using anti-TIGIT mAb monotherapy were not favorable, which prompted a focus on combinational therapies. Some alternative approaches have the potential to avoid limitations, including low penetration, immunogenicity and safety of mAbs. This review addresses the mechanisms underlying TIGIT-mediated immune suppression. Additionally, promising immunotherapeutic approaches against TIGIT, including co-inhibition of TIGIT with other ICs, using small molecule inhibitors, blocking the TIGIT/PVR pathway using CAR-T cells and the current state of clinical trials as well as future directions, are discussed.

Fig. 1. Interaction of TIGIT and CD226 with their ligands.

TIGIT and CD226 are expressed in T and NK cells and appear as transmembrane proteins. Their ligands are expressed in antigen-presenting cells or tumor cells and are also localized to the cell membrane. TIGIT has an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoglobulin tyrosine tail (ITT)-like domain, while CD226 has an ITT-like domain and CD155 has an ITIM. CD155 has a higher affinity for TIGIT than other ligands and is an immune-suppressing receptor like TIGIT. CD226 is an immune-activating receptor whose ligand is CD155, but it can be competed for by TIGIT. Additionally, TIGIT inhibits CD226 by disrupting its dimerization. Fap2 is a special protein ligand for TIGIT, which is secreted by F. nucleatum and can cause suppression of immune cells. Created in https://BioRender.com.

Fig. 2. Synergistic effects of TIGIT and PD-1 immune checkpoints and co-inhibition therapy.

A Both TIGIT and PD-1 inhibit signaling from the immune-activating receptor CD226. PD-1 binds to PD-L1 and recruits SHP2, ultimately leading to the inhibition of intracellular signaling from CD226. TIGIT accomplishes this extracellularly by competing with CD226 and disrupting the structure of the CD226 dimer. B Using antibodies to inhibit the PD-1/PD-L1 pathway increases TIGIT expression, leading to immune inhibition. C Combination of anti-TIGIT and anti-PD-1 antibodies can release the inhibition of CD226 signaling and activate T cells. D Bispecific antibodies (bsAbs) inhibit both TIGIT and PD-1/PD-L1 and bridge immune cells and tumor cells. Created in https://BioRender.com.

Fig. 3. Blocking TIGIT in CAR-T therapy.

CAR on the surface of genetically engineered T cells recognize tumor antigens and induce killing, but binding of TIGIT to CD155 inhibits this effect. Blocking of TIGIT by antibodies or its down-regulation by shRNA can be favorable to activation of CAR-T cell immune function. The combination of TIGIT extracellular domain and activating intracellular domain can promote tumor killing. Created in https://BioRender.com.