Jennifer Bryan

Introduction. Despite prevention and early detection efforts, melanoma incident rates, mortality, and morbidity remain high.¹ One method of treatment is immunotherapy, which stimulates the body’s own immune system to defend against cancer. An important component to that immune response is cytotoxic effector cells, including natural killer (NK) and CD8⁺ T cells, which are often inhibited by cancerous cells. An inhibitory receptor located on both cell types called T-cell immunoglobulin and ITIM domain (TIGIT) is currently being explored as a potential target for immunotherapy.^2-4  Methods. Mean fluorescent intensity, flow cytometry analysis, and histology were used to analyze TIGIT’s effect on cytotoxic effector cells in mouse models, blood smears, and single cell suspensions in order to examine the potential for dual-targeting of TIGIT in both types of cytotoxic effector cells.^2-6 Many studies focused on either NK or CD8⁺ T Cells, though TIGIT displays parallel – perhaps even complementary – functions in both cell types.³ Results. In CD8⁺ T cells located within melanoma tumors, CD226 is downregulated while TIGIT, CD155, and CD112 are upregulated.² This leads to a net inhibition of the cell’s anti-tumor function. Furthermore, TIGIT knockout mice display decreased exhaustion markers and apoptosis on NK cells when compared to wild-type mice.³ This indicates that TIGIT plays a critical role in cancer-mediated cytotoxic effector cell exhaustion. CD8⁺ T cells with TIGIT-based chimeric costimulatory switch receptors (CSRs) containing a TIGIT extracellular domain and a CD28 intracellular domain display increased anti-tumor function, indicating that TIGIT’s inhibitory signal can be converted to a stimulatory signal.⁵ When aged for 22 months, TIGIT-knockout mice display no signs of auto-immunity, which is a common problem with other immune checkpoint blockades.⁶  Conclusions. TIGIT is a promising target for immunotherapy treatment of melanoma because unlike many current immune checkpoint targets, it is located on both CD8⁺ T cells and NK cells. Blocking TIGIT can prevent and even reverse cellular exhaustion in cytotoxic effector cells, which a key step in the proliferation and spread of cancer. Additionally, CSRs have the potential to cause a net increase in cell activity by creating stimulatory signals from TIGIT receptors. Finally, targeting TIGIT does not appear to have the same immune related adverse events associated with other checkpoint blockades. Going forward, research will need to look at the combined impact on cytotoxic effector cells when TIGIT undergoes blockades and CSRs.

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2. Chauvin J, Pagliano O, Fourcade J et al. TIGIT and PD-1 impair tumor antigen–specific CD8+ T cells in melanoma patients. Journal of Clinical Investi 2015;125(5):2046-2058. doi:10.1172/jci80445
3. Zhang Q, Bi J, Zheng X et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol. 2018;19(7):723-732. doi:10.1038/s41590-018-0132-0
4. Sun H, Sun C. The Rise of NK Cell Checkpoints as Promising Therapeutic Targets in Cancer Immunotherapy. Front Immunol. 2019;10. doi:10.3389/fimmu.2019.02354
5. Hoogi S, Eisenberg V, Mayer S, Shamul A, Barliya T, Cohen C. A TIGIT-based chimeric co-stimulatory switch receptor improves T-cell anti-tumor function. J Immunother Cancer. 2019;7(1). doi:10.1186/s40425-019-0721-y
6. Harjunpää H, Blake S, Ahern E et al. Deficiency of host CD96 and PD-1 or TIGIT enhances tumor immunity without significantly compromising immune homeostasis. Oncoimmunology. 2018;7(7):e1445949. doi:10.1080/2162402x.2018.1445949