Dendritic cells accelerate CAR T cells in irradiated tumors through chimeric synapses [RNA-seq]

Sustaining Chimeric Antigen Receptor (CAR) T cell activity in the tumor microenvironment (TME) is a major challenge that continues to hinder the advancement of this therapy for solid tumors. Here we report dramatically enhanced longevity of CAR T cells targeted to irradiated orthotopic lung tumors, leading to durable control in a syngeneic mouse model. CAR T cells robustly infiltrated into irradiated tumors where they maintained elevated expression of cytotoxic effector genes and demonstrated enhanced cytotoxicity. Remarkably, enhanced CAR T cell persistence in irradiated tumors was critically dependent on dendritic cells through a surprising mechanism. Dendritic cells that underwent “antigen-dressing” of tumor-derived target antigens could activate CAR T cells through the chimeric receptor, while resident and infiltrating myeloid subsets that also underwent antigen-dressing did not, suggesting that DCs were unique amongst myeloid cells in the capacity to maintain CAR T cells. Furthermore, tumor irradiation did not enhance CAR T cell activity through depletion of tumor associated macrophages alone, as targeted depletion of CSF1R-dependent myeloid cells had no measurable impact on CAR T cell persistence or tumor control. Rather, these data indicate that tumor irradiation generates conditions conducive for CAR T cells and antigen-dressed dendritic cells to engage effectively. The discovery that a well-tolerated dose of radiation bolsters CAR T cell persistence in solid tumors marks a pivotal advance with significant translational potential, and demonstrates for the first time the indispensable role dendritic cells have in sustaining CAR T cell activity against solid tumors.