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

被引：91

作者：

Jia, Dingjiacheng ^{[1
,2
]}

Wang, Qiwen ^{[2
,3
]}

Qi, Yadong ^{[1
,2
]}

Jiang, Yao ^{[1
,2
]}

He, Jiamin ^{[2
,3
]}

Lin, Yifeng ^{[1
,2
]}

Sun, Yong ^{[1
,2
]}

Xu, Jilei ^{[2
,3
]}

Chen, Wenwen ^{[1
,2
]}

Fan, Lina ^{[1
,2
]}

Yan, Ruochen ^{[2
,3
]}

Zhang, Wang ^{[5
]}

Ren, Guohong ^{[6
]}

Xu, Chaochao ^{[1
,2
]}

Ge, Qiwei ^{[1
,2
]}

Wang, Lan ^{[2
,3
]}

Liu, Wei ^{[7
]}

Xu, Fei ^{[1
,8
]}

Wu, Pin ^{[9
]}

Wang, Yuhao ^{[10
]}

Chen, Shujie ^{[2
,3
,4
]}

Wang, Liangjing ^{[1
,2
,4
]}

机构：

[1] Zhejiang Univ, Affiliated Hosp 2, Sch Med, Dept Gastroenterol, Hangzhou 310058, Zhejiang, Peoples R China

[2] Zhejiang Univ, Inst Gastroenterol, Hangzhou 310058, Zhejiang, Peoples R China

[3] Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Gastroenterol, Hangzhou 310058, Zhejiang, Peoples R China

[4] Zhejiang Univ, Canc Ctr, Hangzhou 310001, Zhejiang, Peoples R China

[5] Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Infect Dis, Hangzhou 310058, Zhejiang, Peoples R China

[6] Zhejiang Univ, Affiliated Hosp 2, Sch Med, Dept Breast Surg, Hangzhou 310058, Zhejiang, Peoples R China

[7] Zhejiang Acad Agr Sci, Inst Plant Protect & Microbiol, Hangzhou 310021, Zhejiang, Peoples R China

[8] Zhejiang Univ, Affiliated Hosp 2, Inst Pharmaceut Biotechnol, Sch Med, Hangzhou 310058, Zhejiang, Peoples R China

[9] Zhejiang Univ, Affiliated Hosp 2, Sch Med, Dept Thorac Surg, Hangzhou 310058, Zhejiang, Peoples R China

[10] Zhejiang Univ, Inst Translat Med, Sch Med, Hangzhou 310029, Zhejiang, Peoples R China

来源：

CELL | 2024年 / 187卷 / 07期

关键词：

TUMOR-ASSOCIATED MACROPHAGES; GUT; SUBSETS; THERAPY;

D O I：

10.1016/j.cell.2024.02.022

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 aPD-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.

引用

页码：1651 / 1665.e21

页数：37

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