Bifidobacterium boosts anti-PD-1 effectiveness through JAK pathway in hepatocellular carcinoma
Ran Huo, Quan-Guo Xu, Yiqing You, Yanlin Chen, Guang-Jian Su, Kun-rong Yang, Yanping Xiao, Xue Zhong, Yanping Li, Pei Sun, Zhao-Lei Cui, Yingying Lin, Jun-ying Guo, Haiyan Xu, Zhao-shuo Chen, Wen-ting Xie, Shaohua Xu, Minyong Chen, Jing Wu, Shijie He, Zhen-zhou Xiao, Yan Chen
Abstract
Hepatocellular carcinoma (HCC) is a prevalent and deadly cancer. Gut microbiota affect tumor immunity and immunotherapy efficacy, but the exact mechanisms are unclear. A study compared gut microbiota in HCC patients and healthy controls (HC) using 16S rDNA analysis and metabolomics. It found higher levels of Bifidobacterium and a positive correlation between Bifidobacterium and isobutyric acid in HC group. Animal models showed that the combination of HC fecal matter and αPD-1 treatment reduced tumor volume more effectively than the combination of HCC fecal matter and αPD-1. The combination of Bifidobacterium or isobutyrate with αPD-1 also decreased tumor size. In vitro, isobutyrate-stimulated CD8 + T cells increased IFN-γ secretion, suppressed liver cancer cells, and downregulated the JAK/STAT3 pathway. Combined treatments increased CD8 + T cells and IFN-γ levels and reduced JAK/STAT3 signaling in the tumor microenvironment. This suggests that Bifidobacterium and isobutyrate can inhibit tumor growth, offering insights into gut microbiota-host interactions and potential strategies to overcome HCC immunotherapy resistance.