The Co-Expression Of Two Immune Complex Molecules, Vista And Tigit, Define A Dysfunctional Cytotoxic T Cell Subset

Background Cancer immunotherapies have proven, over the last decade, to be of extreme importance for long term survival of patients. Specifically, immune checkpoint inhibitors such as anti-CTLA-4 and anti-PD-1/PD-L1 have had tremendous clinical success treating many cancers including melanoma, lung, breast, colon, and bladder cancer. The low response rate (~30%) of these drugs suggest a mechanism of resistance within the tumor microenvironment, and it demonstrates the immense need to study and develop alternative routes to long-term anti-tumor immunity.1V-domain Immunoglobulin Suppressor of T-cell Activation (VISTA) has been shown to be a suppressive molecule in the tumor microenvironment in preclinical models and VISTA’s expression is correlated with poor patient outcome across several cancers.2T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) is a functional receptor expressed on NK cells and T cells that contributes to a suppressive tumor microenvironment by acting on T cells, NK cells, and antigen presenting cells.3 Methods We use flow cytometry to visualize single cell expression of VISTA and TIGIT on CD8+ tumor infiltrating lymphocytes in pre-clinical models. Functional studies include cytotoxic assays as well as intracellular cytokine staining after cell sorting. Results Here we show the expression of these two immune checkpoint molecules, VISTA and TIGIT, across several pre-clinical models, and how their co-expression subsets a distinctly dysfunctional population of cytotoxic T cells. Conclusions Our data provides foundation to study the rejuvenation of this subset of T cells to restore cytotoxic function and therefore, anti-tumor immunity. Trial Registration NA Ethics Approval All in vivo studies were reviewed and approved by Institutional Animal Care and Use Committee (Approval number 2019-2142). Consent NA References Fares CM, Allen EMV, Drake CG, Allison JP \u0026 Hu-Lieskovan S. Mechanisms of resistance to immune checkpoint blockade: why does checkpoint inhibitor immunotherapy not work for all patients?American Society of Clinical Oncology Educational Book 2019;147–164. Xu W, Hieu T, Malarkannan S. \u0026 Wang L. The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol 2018;15:438–446. Manieri NA, Chiang EY \u0026 Grogan JL. TIGIT: A Key Inhibitor of the Cancer Immunity Cycle. Trends Immunol 2017;38:20–28.