TIGIT (T cell immunoglobulin and ITIM domain) is an inhibitory receptor expressed on lymphocytes, including natural killer (NK) cells and various subsets of T cells such as CD4+ T cells, CD8+ T cells, and regulatory T cells. It was discovered in 2009 through genome-wide analysis aiming to identify proteins containing domain structures typical for immunomodulatory receptors. TIGIT consists of one extracellular immunoglobulin variable domain, a type I transmembrane domain, and a short intracellular domain with one immunoreceptor tyrosine-based inhibitory motif (ITIM) and one immunoglobulin tyrosine tail (ITT)-like motif. Its main ligand is CD155, also known as poliovirus receptor (PVR), but it can also bind to CD112 and CD113 with lower affinity. TIGIT plays a significant role in down-regulating T cell and NK cell functions by interacting with these ligands expressed on antigen-presenting cells or tumor cells. This interaction inhibits immune cell responses at multiple steps of the cancer-immunity cycle, such as impairing T cell priming by dendritic cells, preventing tumor cell killing by NK cells and cytotoxic T cells, and enhancing the immune suppressive activity of regulatory T cells. Therefore, TIGIT has emerged as a major target in cancer immunotherapy. Several monoclonal antibodies that block the inhibitory activity of human TIGIT have been developed, and clinical trials are ongoing to investigate TIGIT blockade as a monotherapy or in combination with anti-PD1/PD-L1 antibodies for the treatment of patients with advanced solid malignancies.
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