Wei and Long et al. used CRISPR-Cas9 screening of metabolism-associated genes in an adoptive T cell therapy model and showed that the RNA-degrading enzyme REGNASE-1 greatly increased numbers of tumor-infiltrating CD8+ T cells and antitumor efficacy. Deleting REGNASE-1 enhanced survival and mitochondrial fitness of memory-like CD8+ T cells with retained effector functions. A secondary screen of REGNASE-1-null CD8+ T cells showed that BATF is a key REGNASE-1 target. BATF deletion prevented CD8+ T cell accumulation and mitochondrial vigor, whereas PTPN2 and SOCS1 depletion potentiated the efficacy of REGNASE-1-deficient CD8+ T cells.
Contributed by Paula Hochman
Adoptive cell therapy represents a new paradigm in cancer immunotherapy, but it can be limited by the poor persistence and function of transferred T cells(1). Here we use an in vivo pooled CRISPR-Cas9 mutagenesis screening approach to demonstrate that, by targeting REGNASE-1, CD8(+) T cells are reprogrammed to long-lived effector cells with extensive accumulation, better persistence and robust effector function in tumours. REGNASE-1-deficient CD8(+) T cells show markedly improved therapeutic efficacy against mouse models of melanoma and leukaemia. By using a secondary genome-scale CRISPR-Cas9 screening, we identify BATF as the key target of REGNASE-1 and as a rheostat that shapes antitumour responses. Loss of BATF suppresses the increased accumulation and mitochondrial fitness of REGNASE-1-deficient CD8(+) T cells. By contrast, the targeting of additional signalling 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 tumour immunity and point to avenues for improving the efficacy of adoptive cell therapy for cancer.