De novo NAD+ synthesis contributes to CD8+ T cell metabolic fitness and antitumor function
Jie Wan,
Cheng Cheng,
Jiajia Hu,
Haiyan Huang,
Qiaoqiao Han,
Zuliang Jie,
Qiang Zou,
Jian-Hong Shi,
Xiaoyan Yu
Affiliations
Jie Wan
Central Laboratory, Hebei Collaborative Innovation Center of Tumor Microecological Metabolism Regulation, Affiliated Hospital of Hebei University, Baoding 071000, Hebei Province, China; Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China
Cheng Cheng
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 119 South Fourth Ring Western Road, Fengtai District, Beijing, China
Jiajia Hu
Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Haiyan Huang
Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Qiaoqiao Han
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China
Zuliang Jie
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
Qiang Zou
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China; Corresponding author
Jian-Hong Shi
Central Laboratory, Hebei Collaborative Innovation Center of Tumor Microecological Metabolism Regulation, Affiliated Hospital of Hebei University, Baoding 071000, Hebei Province, China; Corresponding author
Xiaoyan Yu
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China; Corresponding author
Summary: The dysfunction and clonal constriction of tumor-infiltrating CD8+ T cells are accompanied by alterations in cellular metabolism; however, how the cell-intrinsic metabolic pathway specifies intratumoral CD8+ T cell features remains elusive. Here, we show that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD+) via the kynurenine pathway (KP) contributes to the maintenance of intratumoral CD8+ T cell metabolic and functional fitness. De novo NAD+ synthesis is involved in CD8+ T cell metabolism and antitumor function. KP-derived NAD+ promotes PTEN deacetylation, thereby facilitating PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, impaired cell-autonomous NAD+ synthesis limits CD8+ T cell responses in human colorectal cancer samples. Our results reveal that KP-derived NAD+ regulates the CD8+ T cell metabolic and functional state by restricting PTEN activity and suggest that modulation of de novo NAD+ synthesis could restore CD8+ T cell metabolic fitness and antitumor function.
