The co-expression of VISTA and TIGIT on cytotoxic T cells defines subpopulation with altered immunometabolism

Cancer immunotherapies, specifically checkpoint blockade therapies, are extremely successful at treating subpopulations of specific cancers long term. The idea is to disrupt the negative regulation of T cells and restore cytotoxic abilities allowing killing of the cancer cells and formation of memory T cells. This provides immunity that has the potential to last a lifetime against recurring cancer. One major limitation to checkpoint blockade is that it is has limited response rate, one theory as to why this is the case, is that there are multiple non-redundant pathways of regulation of T cell activation. In response to the heterogeneous and suppressive tumor microenvironment, the T cell may present many immune checkpoint proteins simultaneously. Thus, it is important to study the immune checkpoint proteins in context of one another with the goal of developing combinatorial therapies. Here we present the co-expression of two immune checkpoint proteins and how their co-expression results in altered metabolism in cytotoxic T cells. V-domain Immunoglobulin Suppressor of T-cell Activation (VISTA) is a protein with many roles that are still largely undefined across a variety of immune cells in which it is expressed. T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) is a bi-directional receptor that has been reported to have a suppressive intrinsic T cell role when probed with agonistic antibody, the mechanism is yet to be defined. Our data suggest that VISTA and TIGIT are co-expressed in varying amounts across a variety of murine and human cancers and that this co-expression may contribute to an altered metabolic phenotype. Our results give insight to the contribution of multiple checkpoint proteins to the state of the cytotoxic T cell and declare the importance of studying these proteins in context of one another. This data reaffirm the need to study non-redundant pathways of T cell suppression with the goal of developing inhibitors that are more broadly applicable to restore anti-tumor immunity and increase patient survival. Citation Format: Cassandra Gilmour, Seong-Keun (Steve) Yoo, Timothy Chan, Lily Wang. The co-expression of VISTA and TIGIT on cytotoxic T cells defines subpopulation with altered immunometabolism [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr PR02.