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, and Liangjing Wang1

Cell | Volume 187 | 2024 | 1651-1665

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 (Tpex) 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.