GPCR-based pharmacological perturbation screening reveals a universally conserved signal for CAR T cell migration to solid tumors 3363

Description CAR T cell immunotherapy has emerged as a powerful treatment option for hematological malignancies but is largely ineffective in solid tumors. This represents an enormous unmet clinical need because solid tumors constitute approximately 90% of adult human cancers. A key limitation to effective CAR T cell immunotherapy in solid tumors is the physical access of T cells to the target tumor sites. Using an in vitro 3D tumor spheroid model, we discovered a massive directional migration pattern of CAR T cells to the target tumor, reminiscent of insect “swarming” behavior. Notably, the “CAR T cell swarming” pattern was highly conserved among many cancer types. The directional migration pattern of CAR T cells was completely abolished by pretreatment of the cells with pertussis toxin, suggesting the presence of a specific GPCR chemotactic signal. To discover the conserved GPCR chemotactic signal, we developed a high-throughput pharmacological perturbation screening. We identified the Leukotriene B4 receptor, BLT1, as a key mediator of the CAR T cell homing to solid tumors. In vivo, BLT1 overexpression on CAR T cells significantly improved tumor-specific homing and tumor control. Here, we identified a molecular mechanism that could be harnessed to improve the homing of therapeutic T cells to target tumor sites, thereby increasing the efficacy of CAR T cell immunotherapy. Funding Sources Supported by NIH AI147362-01; NIH AI102851; T32GM135134; Breast Cancer Coalition of Rochester Pamela Delp Polashenski MD Trainee Research Grant Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)