Ting, Adrian

Abstract Description CAR-T cell therapy has shown remarkable success in treating hematologic cancers; however, its efficacy in solid tumors remains limited, partly due to tumor heterogeneity, immune suppression within the tumor microenvironment, and inefficient CAR-T cell infiltration. I hypothesize that increasing the sensitivity of tumor cells to cytokine-mediated killing could enhance the therapeutic impact of CAR-T cells in solid tumors. I propose that targeting Adenosine Deaminases Acting on RNA 1 (ADAR1), an enzyme that edits double-stranded RNA (dsRNA) to prevent immune activation, may be one such strategy. ADAR1 balances inflammation by preventing the overactivation of dsRNA sensors such as PKR, MDA5, and RIG-I. However, in the absence of ADAR1, accumulating dsRNA structures will trigger these dsRNA sensors and alter the tumor cell intrinsic response to T cell-derived cytokines, such as IFNγ and TNF. My data provide evidence that inhibition of ADAR1 in tumor cells sensitize them to killing by cytokines, but it remains unclear how signaling from dsRNA sensors crosstalk with those from cytokine receptors to regulate cell survival or death. My study aims to elucidate the interplay between these different signaling pathways in the absence of ADAR1, and how this interplay determines the efficacy of CAR-T cells against solid tumors. My experimental observations could provide insights into novel therapeutic strategies to improve CAR-T cell potency against resistant tumor types. Funding Sources Mayo Clinic Cancer Center Fellowship Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)