Microbial metabolite enhances immunotherapy efficacy by modulating T cell stemness in pan-cancer

Dingjiacheng Jia; Qiwen Wang; Yadong Qi; Yao Jiang; Jiamin He; Yifeng Lin; Yong Sun; Jilei Xu; Wenwen Chen; Lina Fan; Ruochen Yan; Wang Zhang; Guohong Ren; Chaochao Xu; Qiwei Ge; Lan Wang; Wei Liu; Fei Xu; Pin Wu; Yuhao Wang; Shujie Chen; Liangjing Wang

doi:10.1016/j.cell.2024.02.022

Microbial metabolite enhances immunotherapy efficacy by modulating T cell stemness in pan-cancer

Cell. 2024 Mar 28;187(7):1651-1665.e21. doi: 10.1016/j.cell.2024.02.022. Epub 2024 Mar 14.

Authors

Dingjiacheng Jia¹, Qiwen Wang², Yadong Qi¹, Yao Jiang¹, Jiamin He², Yifeng Lin¹, Yong Sun¹, Jilei Xu², Wenwen Chen¹, Lina Fan¹, Ruochen Yan², Wang Zhang³, Guohong Ren⁴, Chaochao Xu¹, Qiwei Ge¹, Lan Wang², Wei Liu⁵, Fei Xu⁶, Pin Wu⁷, Yuhao Wang⁸, Shujie Chen⁹, Liangjing Wang¹⁰

Affiliations

¹ Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310058, China; Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province 310058, China.
² Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province 310058, China; Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang Province 310058, China.
³ Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang Province 310058, China.
⁴ Department of Breast Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310058, China.
⁵ Institute of Plant Protection and Microbiology, Zhejiang Academy of Agriculture Sciences, Hangzhou, Zhejiang Province 310021, China.
⁶ Institute of Pharmaceutical Biotechnology and Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310058, China.
⁷ Department of Thoracic Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310058, China.
⁸ Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China.
⁹ Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province 310058, China; Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang Province 310058, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang Province 310001, China. Electronic address: chenshujie77@zju.edu.cn.
¹⁰ Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310058, China; Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province 310058, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang Province 310001, China. Electronic address: wangljzju@zju.edu.cn.

PMID: 38490195
DOI: 10.1016/j.cell.2024.02.022

Abstract

The immune checkpoint blockade (ICB) response in human cancers is closely linked to the gut microbiota. Here, we report that the abundance of commensal Lactobacillus johnsonii is positively correlated with the responsiveness of ICB. Supplementation with Lactobacillus johnsonii or tryptophan-derived metabolite indole-3-propionic acid (IPA) enhances the efficacy of CD8⁺ T cell-mediated αPD-1 immunotherapy. Mechanistically, Lactobacillus johnsonii collaborates with Clostridium sporogenes to produce IPA. IPA modulates the stemness program of CD8⁺ T cells and facilitates the generation of progenitor exhausted CD8⁺ T cells (T_pex) by increasing H3K27 acetylation at the super-enhancer region of Tcf7. IPA improves ICB responsiveness at the pan-cancer level, including melanoma, breast cancer, and colorectal cancer. Collectively, our findings identify a microbial metabolite-immune regulatory pathway and suggest a potential microbial-based adjuvant approach to improve the responsiveness of immunotherapy.

Keywords: Lactobacillus johnsonii; TCF-1; cancer immunotherapy; gut microbiota; immune checkpoint blockade; indole-3-propionic acid; progenitor-exhausted CD8(+) T cells; tryptophan metabolism.

MeSH terms

CD8-Positive T-Lymphocytes*
Humans
Immune Checkpoint Inhibitors / therapeutic use
Immunotherapy*
Indoles / metabolism
Lactobacillus* / metabolism
Neoplasms* / immunology
Neoplasms* / therapy

Substances

indolepropionic acid
Indoles
Immune Checkpoint Inhibitors