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

Jun Wei, Lingyun Long, Wenting Zheng, Yogesh Dhungana, Seon Ah Lim, Cliff Guy, Yanyan Wang, Yong-Dong Wang, Chenxi Qian, Beisi Xu, Anil Kc, Jordy Saravia, Hongling Huang, Jiyang Yu, John G. Doench, Terrence L. Geiger and Hongbo Chi ()
Additional contact information
Jun Wei: St Jude Children’s Research Hospital
Lingyun Long: St Jude Children’s Research Hospital
Wenting Zheng: St Jude Children’s Research Hospital
Yogesh Dhungana: St Jude Children’s Research Hospital
Seon Ah Lim: St Jude Children’s Research Hospital
Cliff Guy: St Jude Children’s Research Hospital
Yanyan Wang: St Jude Children’s Research Hospital
Yong-Dong Wang: St Jude Children’s Research Hospital
Chenxi Qian: St Jude Children’s Research Hospital
Beisi Xu: St Jude Children’s Research Hospital
Anil Kc: St Jude Children’s Research Hospital
Jordy Saravia: St Jude Children’s Research Hospital
Hongling Huang: St Jude Children’s Research Hospital
Jiyang Yu: St Jude Children’s Research Hospital
John G. Doench: Broad Institute of Harvard and MIT
Terrence L. Geiger: St Jude Children’s Research Hospital
Hongbo Chi: St Jude Children’s Research Hospital

Nature, 2019, vol. 576, issue 7787, 471-476

Abstract: Abstract Adoptive cell therapy represents a new paradigm in cancer immunotherapy, but it can be limited by the poor persistence and function of transferred T cells1. 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.

Date: 2019
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DOI: 10.1038/s41586-019-1821-z

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