IL-36γ armored CAR T cells reprogram neutrophils to induce endogenous antitumor immunity

Abstract

Chimeric antigen receptor (CAR) T cells are ineffective against solid tumors due to obstacles of antigen heterogeneity and the immunosuppressive tumor microenvironment (TME). Previous efforts focused on enhancing cytotoxicity and persistence of CAR T cells, while the feasibility of improving their therapeutic efficacy by leveraging the modulatory effects of CAR T cells on host anti-tumor immunity remains unclear. Here, we report that IL-36γ armored CAR T cells eradicate primary solid tumors and enable rejection of rechallenged antigen-negative tumors. IL-36γ armored CAR T cells favorably modulate the TME and reprogram unique neutrophil subsets with tumoricidal ability and antigen-(cross) presenting functions, resulting in the induction of endogenous T cells recognizing tumor antigens beyond CAR-targeted antigens. Our study demonstrates that neutrophil engagement by CAR T cells is a critical step in the establishment of the cancer-immunity cycle and introduces a broadly applicable method to overcome key barriers to adoptive cell therapies for solid tumors.

Keywords: CAR T cells; IL-36γ; anti-tumor neutrophils; antigen heterogeneity; antigen-presenting; cancer-immunity cycle; epitope spreading; immunotherapy; solid tumors.