Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy.

Abstract

Adoptive cell therapy represents a new paradigm in cancer immunotherapy but can be limited by poor persistence and function of transferred T cells1. Here, through an in vivo pooled CRISPR-Cas9 mutagenesis screening, we demonstrate that CD8+ T cells are reprogrammed to long-lived effector cells with extensive accumulation, better persistence and robust effector function in tumors by targeting Regnase-1. Regnase-1-deficient CD8+ T cells show markedly improved therapeutic efficacy against mouse melanoma and leukemia. Through a secondary genome-scale CRISPR-Cas9 screening, we identify BATF as the key target of Regnase-1 and a rheostat in shaping antitumor responses. Loss of BATF suppresses the elevated accumulation and mitochondrial fitness of Regnase-1-deficient CD8+ T cells. Conversely, we reveal that targeting additional signaling factors including PTPN2 and SOCS1 improves the therapeutic efficacy of Regnase-1-deficient CD8+ T cells. Our findings suggest that T-cell persistence and effector function can be coordinated in tumor immunity and point to new avenues to improve the efficacy of adoptive cell therapy for cancer.