Tumor irradiation promotes antigen dressing of dendritic cells to enhance CAR T cell persistence and efficacy in lung metastases

Abstract Metastatic solid tumors remain the principal cause of cancer mortality worldwide. High tumor burden impairs responses to chimeric antigen receptor (CAR) T cell therapy, yet off-tumor toxicity limits the doses that can be safely delivered. Strategies to selectively enhance CAR T cell activity at tumor sites could widen the therapeutic window. Using syngeneic models of extensive metastatic lung adenocarcinoma and melanoma, we show that 8 Gy of tumor irradiation significantly enhanced CAR T cell persistence in a manner critically dependent on dendritic cells (DCs). Irradiation promoted trogocytic antigen dressing of tumor antigens onto DCs, which then expanded CAR T cells through the chimeric receptor. Without functional DCs, irradiation failed to sustain CAR T cell persistence and tumors relapsed. Irradiation increased CAR T cell numbers within tumors but not in adjacent normal lung tissue that also expressed target antigen, conferring robust control of tumor without increased toxicity. These data define a mechanistic basis and rationale for combining radiotherapy with CAR T cell therapy.