Project Grant F31CA310473

OVERCOMING ADENOSINE-MEDIATED SUPPRESSION TO ENHANCE THE ANTITUMOR EFFICACY OF ENGINEERED T CELL THERAPY - SUMMARY: OVARIAN CANCER IS THE DEADLIEST GYNECOLOGIC MALIGNANCY IN THE UNITED STATES, WITH MORE THAN 15,000 DEATHS EACH YEAR AND SURVIVAL RATES THAT HAVE IMPROVED LITTLE OVER THE PAST THREE DECADES. A MAJOR BARRIER TO THERAPEUTIC SUCCESS IS THE PROFOUNDLY IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT (TME), WHICH LIMITS THE PERSISTENCE AND FUNCTION OF ANTITUMOR T CELLS. ENGINEERED T CELL THERAPIES, INCLUDING T CELLS EXPRESSING CHIMERIC ANTIGEN RECEPTORS OR HIGH-AFFINITY T CELL RECEPTORS (TCR), HAVE SHOWN PROMISING ACTIVITY IN PRECLINICAL OVARIAN CANCER MODELS. MESOTHELIN-SPECIFIC TCR-ENGINEERED T CELLS ACCUMULATE IN OVARIAN TUMORS, DELAY DISEASE PROGRESSION, AND EXTEND SURVIVAL IN MICE. HOWEVER, THEIR EFFICACY IS QUICKLY LIMITED BY METABOLIC DYSFUNCTION, INHIBITORY RECEPTOR SIGNALING, AND IMPAIRED PERSISTENCE. A DOMINANT SUPPRESSIVE PATHWAY WITHIN SOLID TUMORS INVOLVES HYPOXIA-INDUCED ACCUMULATION OF EXTRACELLULAR ADENOSINE. ELEVATED ADENOSINE CONCENTRATIONS SIGNAL THROUGH THE ADENOSINE A2A RECEPTOR (A2AR) TO SUPPRESS T CELL PROLIFERATION, CYTOKINE PRODUCTION, AND CYTOTOXICITY, AND CORRELATE WITH POOR PROGNOSIS IN HIGH- GRADE SEROUS OVARIAN CARCINOMA. PRELIMINARY DATA FROM MY WORK DEMONSTRATE THAT A2AR INHIBITION DECREASES SUPPRESSIVE MACROPHAGE SUBSETS IN VIVO, RESTRAINS OVARIAN TUMOR-CELL GROWTH IN VITRO, AND ENHANCES THE FUNCTION OF MESOTHELIN-SPECIFIC TCR-ENGINEERED T CELLS. THESE FINDINGS SUGGEST THAT A2AR SIGNALING OPERATES THROUGH MULTIPLE PATHWAYS THAT CONVERGE TO LIMIT ENGINEERED T-CELL EFFICACY. HOWEVER, THE MECHANISMS BY WHICH A2AR BLOCKADE RESHAPES THE SUPPRESSIVE TME AND IMPROVES ENGINEERED T-CELL PERSISTENCE AND FUNCTION IN OVARIAN CANCER REMAIN INCOMPLETELY DEFINED. THE OVERARCHING GOAL OF THIS PROPOSAL IS TO DETERMINE HOW DISRUPTING A2AR SIGNALING ENHANCES ANTITUMOR IMMUNITY AND IMPROVES THE EFFICACY OF MESOTHELIN-SPECIFIC TCR-ENGINEERED T CELLS. AIM 1 WILL DEFINE HOW A2AR BLOCKADE REPROGRAMS TUMOR CELLS AND SUPPRESSIVE MYELOID POPULATIONS AND WHETHER IT DISRUPTS MACROPHAGE AND T CELL SUPPRESSIVE INTERACTIONS. AIM 2 WILL DETERMINE HOW A2AR INHIBITION AFFECTS THE PHENOTYPE, PERSISTENCE, AND ANTITUMOR FUNCTION OF ENGINEERED T CELLS, INCLUDING DURING CELL MANUFACTURING. TOGETHER, THESE STUDIES WILL PROVIDE MECHANISTIC INSIGHT INTO HOW A2AR SIGNALING LIMITS ENGINEERED T CELL THERAPY AND ESTABLISH A TRANSLATIONAL RATIONALE FOR COMBINING A2AR INHIBITION WITH ADOPTIVE T CELL STRATEGIES IN OVARIAN CANCER.