2. Academic Validation
  3. De novo NAD+ synthesis contributes to CD8+ T cell metabolic fitness and antitumor function

De novo NAD+ synthesis contributes to CD8+ T cell metabolic fitness and antitumor function

  • Cell Rep. 2023 Dec 1;42(12):113518. doi: 10.1016/j.celrep.2023.113518.
Jie Wan 1,  Cheng Cheng 2,  Jiajia Hu 3,  Haiyan Huang 4,  Qiaoqiao Han 5,  Zuliang Jie 6,  Qiang Zou 7,  Jian-Hong Shi 8,  Xiaoyan Yu 9
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 119 South Fourth Ring Western Road, Fengtai District, Beijing, China.
  • 3 Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 4 Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 5 Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
  • 6 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.
  • 7 Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China. Electronic address: qzou1984@sjtu.edu.cn.
  • 8 Central Laboratory, Hebei Collaborative Innovation Center of Tumor Microecological Metabolism Regulation, Affiliated Hospital of Hebei University, Baoding 071000, Hebei Province, China. Electronic address: shijianhong@hbu.edu.cn.
  • 9 Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China. Electronic address: yuxy@shsmu.edu.cn.
PMID: 38041812 DOI: 10.1016/j.celrep.2023.113518
Abstract

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.

Keywords

CP: Cancer; CP: Metabolism.

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