Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8+ T cell immunity

  • Cell Metab. 2021 May 4;33(5):988-1000.e7. doi: 10.1016/j.cmet.2021.03.002.
Yao He  1 ,  Liuhui Fu  1 ,  Yiping Li  2 ,  Wenyan Wang  1 ,  Mingli Gong  2 ,  Jing Zhang  1 ,  Xin Dong  2 ,  Jiaoyan Huang  1 ,  Quanbo Wang  3 ,  Charles R Mackay  4 ,  Yang-Xin Fu  5 ,  Yun Chen  6 ,  Xiaohuan Guo  7
Affiliations
  • 1. Institute for Immunology, School of Medicine, Tsinghua University, Beijing 100084, China; Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China.
  • 2. Institute for Immunology, School of Medicine, Tsinghua University, Beijing 100084, China.
  • 3. School of Pharmaceutical Sciences, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250014, China.
  • 4. School of Pharmaceutical Sciences, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250014, China; Department of Microbiology, Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Melbourne 3800, Australia.
  • 5. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
  • 6. Department of Immunology, Key Laboratory of Immune Microenvironment and Disease, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China; Research center for clinical oncology, Jiangsu Cancer Hospital, the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210018, China.
  • 7. Institute for Immunology, School of Medicine, Tsinghua University, Beijing 100084, China; Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China. Electronic address: [email protected].
PMID: 33761313 DOI: 10.1016/j.cmet.2021.03.002
Abstract

Recent studies in both mice and humans have suggested that gut microbiota could modulate tumor responsiveness to chemo- or immunotherapies. However, the underlying mechanism is not clear yet. Here, we found that gut microbial metabolites, especially butyrate, could promote the efficacy of oxaliplatin by modulating CD8+ T cell function in the tumor microenvironment. Butyrate treatment directly boosted the antitumor cytotoxic CD8+ T cell responses both in vitro and in vivo in an ID2-dependent manner by promoting the IL-12 signaling pathway. In humans, the oxaliplatin responder Cancer patients exhibited a higher amount of serum butyrate than did non-responders, which could also increase ID2 expression and function of human CD8+ T cells. Together, our findings suggest that the gut microbial metabolite butyrate could promote antitumor therapeutic efficacy through the ID2-dependent regulation of CD8+ T cell immunity, indicating that gut microbial metabolites could be effective as a part of Cancer therapy.

Keywords
CD8+ T cell; ID2; IL-12; antitumor therapy efficacy; butyrate; gut microbial metabolites.
Products