TIGIT Immune Checkpoint Molecule for Drug Development
Immune Checkpoint TIGIT
TIGIT (T cell immunoglobulin and ITIM domain), also known as VSig9, Vstm3, or WUCAM, is an inhibitory receptor member of the CD28 family. TIGIT binds to CD155 (PVR or Necl-5) with high affinity and weakly interacts with CD112 (PVRL2, nectin-2). TIGIT also competes with other counterparts, CD266 (DNAM-1) or CD96, to exert its immunosuppressive effects. To learn more about TIGIT-involved pathways, please visit TIGIT and CD155 pathway.
Table.1 Immune checkpoint TIGIT.
Cell type affected
Function of ligand-receptor interaction
T cells, NK cells
CD155 (PVR or Necl-5),
CD112 (PVRL2 or nectin-2)
CD96 and TIGIT exert immunosuppressive effects by competing with CD226 for CD155. TIGIT-Fc fusion protein inhibits T cell activation by generating regulatory DCs.
Structure of TIGIT
TIGIT gene encodes a 244-amino acid transmembrane glycoprotein. The TIGIT protein has a similar structure with the larger poliovirus receptor (PVR)/nectin family of molecules, highly conserved between the mouse and human. TIGIT contains an extracellular IgV domain, a type 1 transmembrane region, a cytoplasmic tail that harbors an ITAM, and an immunoglobulin tail tyrosine (ITT)-like motif.
Expression of TIGIT
TIGIT is widely expressed on NK cells and T cells, specifically those of a subset of regulatory T cells such as activated, memory, and follicular T helper cells.
Function of TIGIT
Early studies have suggested that TIGIT indirectly suppresses immune responses via interacting with CD155 on DCs. Specifically, the engagement of TIGIT with CD155 on DCs induces phosphorylation of CD155 and Erk, increases the secretion of IL-10, further inhibiting T cell responses indirectly. Subsequent studies show that TIGIT also directly suppresses T cell function by competing with CD226. It directly inhibits NK cytotoxicity, granule polarization, and cytokine secretion and inhibits T cell proliferation, cytokine production, and TCR signaling in a cell-intrinsic manner.
Fig.1 TIGIT mechanism of action. (Harjunpää, 2020)
Clinical Development of Drugs Targeting TIGIT
Targeting TIGIT as a cancer treatment strategy attracts the pharmaceutical field’s attention, especially combined with ant-PD-1/PD-L1 mAb. It has been confirmed that TIGIT and PD-1 are upregulated in a 15-gene signature of multiple tumor-associated T cells, especially in colon, endometrial, breast, and renal clear cell carcinoma. Besides, combinatorial blockade of TIGIT and PD-1 can enhance the proliferation and cytokine production of CD8+ TILs in patients with melanoma. Therefore, dual blockade of either TIGIT with PD-1 or with TIM-3 might enhance antitumor potency and induce tumor regression. Several TIGIT-targeting therapeutics are currently in early phase clinical trials.
Services at Creative Biolabs
Creative Biolabs is a well-recognized expert who supports a broad range of drug development projects for immune checkpoints. Currently, a series of custom services for immune checkpoint molecule TIGIT is available at Creative Biolabs, including but not limited to: