Investigating Functional Synergy Between PD-1 and TIGIT in Anti-Tumor Immunity and Autoimmunity

Abstract

Anti-PD-1 therapy has emerged as a promising therapeutic for cancer. PD-1 blockade can increase tumor clearance in pre-clinical mouse models and this has translated to therapy with FDA approval of PD-1 pathway inhibitors for cancer immunotherapy. However, this therapy only works in a subset of patients and for only a subset of cancers. Thus, targeting multiple co-inhibitory pathways seems to be a promising strategy to increase response to immunotherapy. TIGIT is another co-inhibitory receptor expressed on a variety of cells including different T-cell subsets. Both PD-1 and TIGIT are expressed in cancer and chronic infections leading to T cell dysfunction. There have been some studies showing synergy between PD-1 and TIGIT in the context of anti-tumor immunity in mice treated with antibody blockade. However, the mechanism of synergy is unknown. The goal of this thesis is to understand the mechanism of this synergy and identify different cell types involved in tumor clearance using conditional PD-1/TIGIT double knockout mouse models. To achieve this goal, we identified a tumor model that could be used to study the synergy in conditional knockout mice. Since immunotherapy is also associated with a high frequency of immune-related side effects in patients and PD-1 and TIGIT also regulate T cell tolerance, we also investigated the autoimmune phenotype in these mice using the experimental autoimmune encephalomyelitis (EAE) model of autoimmunity. Our studies show that inhibiting PD-1 and TIGIT does not cause more severe disease as compared to inhibiting PD-1 alone. We further studied the phenotype of Tregs from different conditional knockout mice by in vitro methods. Our findings provide insights relevant for development of strategies to improve anti-tumor response while minimizing autoimmune side effects.