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

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Pub Date : 2024-03-28 Epub Date: 2024-03-14 DOI:10.1016/j.cell.2024.02.022

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

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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.

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微生物代谢物通过调节泛癌中的 T 细胞干性提高免疫疗法的疗效

人类癌症的免疫检查点阻断（ICB）反应与肠道微生物群密切相关。在这里，我们报告了共生乳酸杆菌约翰逊氏菌的丰度与 ICB 反应性呈正相关。补充约翰逊乳杆菌或色氨酸衍生代谢产物吲哚-3-丙酸（IPA）可增强 CD8+ T 细胞介导的 αPD-1 免疫疗法的疗效。从机理上讲，约翰逊乳杆菌与梭状芽孢杆菌合作产生了IPA。IPA 可调节 CD8+ T 细胞的干性程序，并通过增加 Tcf7 超级增强区的 H3K27 乙酰化促进原代衰竭 CD8+ T 细胞（Tpex）的生成。IPA 在泛癌症水平上提高了 ICB 反应性，包括黑色素瘤、乳腺癌和结直肠癌。总之，我们的研究结果确定了微生物代谢物-免疫调节途径，并提出了一种潜在的基于微生物的辅助方法来提高免疫疗法的反应性。

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.