2. Academic Validation
  3. Nicotinamide metabolism face-off between macrophages and fibroblasts manipulates the microenvironment in gastric cancer

Nicotinamide metabolism face-off between macrophages and fibroblasts manipulates the microenvironment in gastric cancer

  • Cell Metab. 2024 Jun 18:S1550-4131(24)00189-X. doi: 10.1016/j.cmet.2024.05.013.
Yu Jiang 1,  Yawen Wang 1,  Guofeng Chen 1,  Fei Sun 1,  Qijing Wu 1,  Qiong Huang 1,  Dongqiang Zeng 1,  Wenjun Qiu 1,  Jiao Wang 1,  Zhiqi Yao 1,  Bishan Liang 1,  Shaowei Li 1,  Jianhua Wu 1,  Na Huang 1,  Yuanyuan Wang 1,  Jingsong Chen 2,  Xiaohui Zhai 3,  Li Huang 4,  Beibei Xu 1,  Masami Yamamoto 5,  Tetsuya Tsukamoto 6,  Sachiyo Nomura 7,  Wangjun Liao 8,  Min Shi 9
Affiliations

Affiliations

  • 1 Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 2 Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 3 Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 4 Department of Oncology, First Affiliated Hospital, Gannan Medical University, Ganzhou, China; Jiangxi Clinical Medical Research Center for Cancer, Ganzhou, China.
  • 5 Laboratory of Physiological Pathology, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Tokyo, Japan.
  • 6 Department of Diagnostic Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
  • 7 Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 8 Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Cancer Center, the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China. Electronic address: nfyyliaowj@163.com.
  • 9 Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. Electronic address: nfyyshimin@163.com.
PMID: 38897198 DOI: 10.1016/j.cmet.2024.05.013
Abstract

Immune checkpoint blockade has led to breakthroughs in the treatment of advanced gastric Cancer. However, the prominent heterogeneity in gastric Cancer, notably the heterogeneity of the tumor microenvironment, highlights the idea that the antitumor response is a reflection of multifactorial interactions. Through transcriptomic analysis and dynamic plasma sample analysis, we identified a metabolic "face-off" mechanism within the tumor microenvironment, as shown by the dual prognostic significance of nicotinamide metabolism. Specifically, macrophages and fibroblasts expressing the rate-limiting Enzymes nicotinamide phosphoribosyltransferase and nicotinamide N-methyltransferase, respectively, regulate the nicotinamide/1-methylnicotinamide ratio and CD8+ T cell function. Mechanistically, nicotinamide N-methyltransferase is transcriptionally activated by the Notch pathway transcription factor RBP-J and is further inhibited by macrophage-derived extracellular vesicles containing nicotinamide phosphoribosyltransferase via the SIRT1/NICD axis. Manipulating nicotinamide metabolism through autologous injection of extracellular vesicles restored CD8+ T cell cytotoxicity and the anti-PD-1 response in gastric Cancer.

Keywords

crosstalk; face-off; fibroblast; gastric cancer; immune checkpoint blockade; macrophage; nicotinamide metabolism; tumor microenvironment.

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