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, Hongbo Chi

Research output: Contribution to journalArticlepeer-review

241 Scopus citations

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.

Original languageEnglish
Pages (from-to)471-476
Number of pages6
JournalNature
Volume576
Issue number7787
DOIs
StatePublished - 19 Dec 2019

Bibliographical note

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.

Fingerprint

Dive into the research topics of 'Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy'. Together they form a unique fingerprint.

Cite this