NR4A1 transcriptionally regulates the differentiation of stem-like CD8+ T cells in the tumor microenvironment
Jing Hao,
Ruifeng Li,
Xiaohong Zhao,
Xinwei Liu,
Xiang Chen,
Tian Xie,
Xiaoli Li,
Chenjun Yao,
Qinli Sun,
Kun Wei,
Mengting Gou,
Xinxin Chi,
Wei Xu,
Ling Ni,
Chen Dong
Affiliations
Jing Hao
Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China
Ruifeng Li
Institute for Immunology, Tsinghua University, Beijing, China
Xiaohong Zhao
Institute for Immunology, Tsinghua University, Beijing, China
Xinwei Liu
Institute for Immunology, Tsinghua University, Beijing, China
Xiang Chen
Institute for Immunology, Tsinghua University, Beijing, China
Tian Xie
Institute for Immunology, Tsinghua University, Beijing, China
Xiaoli Li
Institute for Immunology, Tsinghua University, Beijing, China
Chenjun Yao
Shanghai Jiao Tong University, School of Medicine, Shanghai, China
Qinli Sun
Institute for Immunology, Tsinghua University, Beijing, China
Kun Wei
Institute for Immunology, Tsinghua University, Beijing, China
Mengting Gou
Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China
Xinxin Chi
Institute for Immunology, Tsinghua University, Beijing, China
Wei Xu
Institute for Immunology, Tsinghua University, Beijing, China
Ling Ni
Institute for Immunology, Tsinghua University, Beijing, China
Chen Dong
Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China; Westlake University School of Medicine, Hangzhou, Zhejiang, China; Corresponding author
Summary: CD8+ T cells are rendered exhausted in tumor and chronic infection. Among heterogeneous exhausted T cells, a subpopulation of progenitor-like (Tpex) cells have been found important for long-term tumor or pathogen control and are also the main responders in immunotherapy. Using an RFP reporter mouse for the orphan nuclear receptor NR4A1, originally characterized as critical in T cell dysfunction, we discover that the reporter is highly expressed in Tpex cells in tumor and chronic infection. Enforced expression of Nr4a1 promotes Tpex cell accumulation, whereas tumor control is improved after Nr4a1 deletion, associated with increased effector function but decreased long-term maintenance of CD8+ T cells. Integrating chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) analysis, NR4A1 is found to bind and promote the expression of Tpex-related genes, as well as suppress terminal differentiation-associated genes. This study therefore has identified a key role of NR4A1 in Tpex regulation and provides a promising target for immunotherapy.
