2. Academic Validation
  3. Microbial metabolite butyrate promotes anti-PD-1 antitumor efficacy by modulating T cell receptor signaling of cytotoxic CD8 T cell

Microbial metabolite butyrate promotes anti-PD-1 antitumor efficacy by modulating T cell receptor signaling of cytotoxic CD8 T cell

  • Gut Microbes. 2023 Dec;15(2):2249143. doi: 10.1080/19490976.2023.2249143.
Xinhai Zhu 1,  Ke Li 2,  Guichao Liu 3 4,  Ruan Wu 5,  Yan Zhang 1,  Siying Wang 6,  Meng Xu 1,  Ligong Lu 7,  Peng Li 7 8
Affiliations

Affiliations

  • 1 Department of Oncology, First Affiliated Hospital, Jinan University, Guangzhou, China.
  • 2 Department of Geriatrics, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
  • 3 Department of Head and Neck Breast Radiotherapy, The First People's Hospital of Foshan City, Foshan, China.
  • 4 The First Affiliated Hospital, Jinan University, Guangzhou, China.
  • 5 Center for Disease Control and Prevention, Anhui Provincial Center for Disease Control and Prevention, Hefei, China.
  • 6 Department of Breast Surgery, First Affiliated Hospital, Jinan University, Guangzhou, China.
  • 7 Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Zhuhai, China.
  • 8 The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, China.
PMID: 37635362 DOI: 10.1080/19490976.2023.2249143
Abstract

Recent studies have demonstrated that the antitumor immunity of immune cells can be modulated by gut microbiota and their metabolites. However, the underlying mechanisms remain unclear. Here, we showed that the serum butyric acid level is positively correlated with the expression of programmed cell death-1 (PD-1) on circulating CD8+ and Vγ9 Vδ2 (Vδ2+) T cells in patients with non-small cell lung Cancer (NSCLC). Responder NSCLC patients exhibited higher levels of serum acetic acid, propionic acid, and butyric acid than non-responders. Depletion of the gut microbiota reduces butyrate levels in both feces and serum in tumor-bearing mice. Mechanistically, butyrate increased histone 3 lysine 27 acetylation (H3K27ac) at the promoter region of Pdcd1 and CD28 in human CD8+ T cells, thereby promoting the expression of PD-1/CD28 and enhancing the efficacy of anti-PD-1 therapy. Butyrate supplementation promotes the expression of antitumor cytokines in cytotoxic CD8+ T cells by modulating the T-cell receptor (TCR) signaling pathway. Collectively, our findings reveal that the metabolite butyrate of the gut microbiota facilitates the efficacy of anti-PD-1 immunotherapy by modulating TCR signaling of cytotoxic CD8 T cells, and is a highly promising therapeutic biomarker for enhancing antitumor immunity.

Keywords

Gut microbiota; PD-1; T cell receptor; anti-tumor immunity; butyrate.

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