Investigating tissue-resident memory T cell differentiation of CAR T cells reveals an unexpected role for CD69

Abstract Adoptive cell therapy using chimeric antigen receptor-expressing (CAR) CD8+ T cells has revolutionized the treatment of liquid tumors; however, CAR have had more limited success against solid tumors. tissue-resident memory (Trm), which are characterized by surface expression CD69 and CD103 a unique transcription factor circuit, found within tumors associated with improved tumor control. However, it is unclear whether adopt Trm features in microenvironment how enhancing differentiation might impact their efficacy Using murine model MC38, we identified both CD69+CD103- CD69+CD103+ subsets that express signature genes. To examine if follow similar pattern, human carcinoembryonic (hCEA)-specific either CD28 or 4-1BB costimulatory domain were transferred into hosts bearing MC38-hCEA We drove expansion population while delaying marker compared to non-CAR cells. The persistence CD69-CD103-subset strongly correlated number hCEA-CD28 tumor. CD69-CD103- proliferative expressed lower levels markers dysfunction, including PD-1 LAG3. hypothesized could negatively regulate proliferation function; indeed, deletion enhanced accumulation In summary, signaling delayed resulting prolonged proliferation. NIH 7R01AI153096