2. Academic Validation
  3. The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer

The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer

  • Cell Metab. 2022 Apr 5;34(4):581-594.e8. doi: 10.1016/j.cmet.2022.02.010.
Hai Wang 1,  Xingyu Rong 2,  Gan Zhao 2,  Yifan Zhou 1,  Yi Xiao 1,  Ding Ma 1,  Xi Jin 1,  Yonglin Wu 2,  Yuchen Yan 2,  Hao Yang 2,  Yuan Zhou 2,  Manning Qian 2,  Chen Niu 2,  Xin Hu 1,  Da-Qiang Li 1,  Qingyun Liu 3,  Yumei Wen 2,  Yi-Zhou Jiang 4,  Chao Zhao 5,  Zhi-Ming Shao 6
Affiliations

Affiliations

  • 1 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China.
  • 2 MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200032, P.R. China.
  • 3 Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
  • 4 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. Electronic address: yizhoujiang@fudan.edu.cn.
  • 5 MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200032, P.R. China. Electronic address: czhao@fudan.edu.cn.
  • 6 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. Electronic address: zhimingshao@fudan.edu.cn.
PMID: 35278352 DOI: 10.1016/j.cmet.2022.02.010
Abstract

Immunotherapy has achieved limited success in patients with triple-negative breast Cancer (TNBC), an aggressive disease with a poor prognosis. Commensal microbiota have been proven to colonize the mammary gland, but whether and how they modulate the tumor microenvironment remains elusive. We performed a multiomics analysis of a cohort of patients with TNBC (n = 360) and found genera under Clostridiales, and the related metabolite trimethylamine N-oxide (TMAO) was more abundant in tumors with an activated immune microenvironment. Patients with higher plasma TMAO achieved better responses to immunotherapy. Mechanistically, TMAO induced Pyroptosis in tumor cells by activating the endoplasmic reticulum stress kinase PERK and thus enhanced CD8+ T cell-mediated antitumor immunity in TNBC in vivo. Collectively, our findings offer new insights into microbiota-metabolite-immune crosstalk and indicate that microbial metabolites, such as TMAO or its precursor choline, may represent a novel therapeutic strategy to promote the efficacy of immunotherapy in TNBC.

Keywords

antitumor immunity; commensal microbiota; immunotherapy; microbial metabolite; pyroptosis; trimethylamine N-oxide; triple-negative breast cancer.

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