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.
Author Info: (1) Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. (2) Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. (3) Depa
Author Info: (1) Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. (2) Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. (3) Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA. (4) Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. (5) Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. (6) Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. (7) Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. (8) Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA. (9) Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA. (10) Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA. (11) Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. (12) Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. (13) Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. (14) Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA. (15) Broad Institute of Harvard and MIT, Cambridge, MA, USA. (16) Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA. (17) Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. hongbo.chi@stjude.org.
