Effective eradication of brain tumors requires synergy between CAR T cells and brain tumor microenvironment

Understanding interactions between the tumor immune microenvironment (TIME) and adoptively transferred immune cells is critical for developing successful T-cell based immunotherapies. Here we investigated the impact of TIME and chimeric antigen receptor (CAR) design on anti-glioma activity of CAR T-cells. We show that CD28-based B7-H3 CAR T-cells have superior efficacy compared to all other CAR designs in murine glioma model. Next, we demonstrate that anti-tumor response of CD28-based CAR T-cells is associated with steady activation of endogenous macrophages and T-cells, which leads to potent anti-tumor responses. However, myeloid and lymphoid populations with predominantly exhausted and/or suppressive signatures infiltrate tumors treated with sub-optimal CARs. We also show that pretreatment with CSF1R inhibitor, which globally depletes brain macrophages, completely abrogates CAR T-cell anti-tumor activity. Our findings show that CAR signaling domains can induce potent pro-inflammatory and immunosuppressive responses, which drive the efficacy of CAR T cell therapy.