Blockade of the adenosine A2A receptor enhances the anti-tumor efficacy of engineered T cell therapy 3359

Abstract Description Ovarian cancer has persistent poor survival rates, highlighting an urgent need for innovative treatments. Engineered T cell therapies expressing high-affinity tumor-specific T cell receptors (TCRs) have shown promise in preclinical solid tumor models. Indeed, we previously demonstrated that TCR T cells targeting mesothelin significantly extend survival in an immune-competent mouse model of advanced ovarian cancer. However, the immunosuppressive tumor microenvironment (TME) often leads to T cell dysfunction, limiting therapeutic efficacy. In hypoxic TMEs, adenosine is elevated and activates the A2A receptor (A2AR), which suppresses T cell function. Notably, high adenosine levels are correlated with poor prognosis in ovarian cancer patients. Although A2AR inhibitors are under clinical investigation, immunotherapies that enhance endogenous antitumor T cell responses have yielded disappointing results in ovarian cancer. We hypothesized that combining engineered T cells and A2AR blockade could enhance antitumor efficacy and persistence. Our preliminary data confirm that a selective A2AR inhibitor restores engineered T cell function in vitro. Ongoing studies are evaluating how disrupting A2AR signaling influences TCR T cell phenotype and function in vivo. Results from this study could provide insights for more effective T cell therapies across solid tumors that share adenosine-mediated immune suppression. Funding Sources Supported by NCI T32 CA 009109, K22 CA 266737-01A1 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)