Abstract

 

Antibody-based therapeutics targeting the inhibitory receptors PD-1, PD-L1, or CTLA-4 have shown remarkable clinical progress on several cancers. However, most patients do not benefit from these therapies. Thus, many efforts are being made to identify new immune checkpoint receptor-ligand pathways that are alternative targets for cancer immunotherapies. Nectin and nectin-like molecules are widely expressed on several types of tumor cells and play regulatory roles in T- and NK-cell functions. TIGIT, a co-inhibitory receptor that interacts with CD155 (PVR), CD112 (Nectin-2), CD113 (Nectin-3), and Nectin-4 (PVRL4) is an immune checkpoint in T- and NK-cell activation. TIGIT shares ligands with CD226 (DNAM-1), CD96 (TACTILE), and CD112R (PVRIG). The integrated signals formed by the complex interaction between nectin and nectin-like molecules and their cognate receptors contribute to regulating immune-cell functions. Several clinical trials are currently evaluating the efficacy of anti-TIGIT and anti-CD112R blockades for treating patients with solid tumors. However, many questions still need to be answered in order to fully understand the dynamics and functions of these receptor networks. This review addresses the rationale behind targeting TIGIT, CD226, CD96, and CD112R to regulate T- and NK-cell functions and discusses their potential application in cancer immunotherapy.