| First Author | Wei J | Year | 2019 |
| Journal | Nature | Volume | 576 |
| Issue | 7787 | Pages | 471-476 |
| PubMed ID | 31827283 | Mgi Jnum | J:293307 |
| Mgi Id | MGI:6445912 | Doi | 10.1038/s41586-019-1821-z |
| Citation | Wei J, et al. (2019) Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy. Nature 576(7787):471-476 |
| abstractText | 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. |
