Synergistic activity of Enterococcus Faecium-induced ferroptosis via expansion of IFN-γ+CD8+ T cell population in advanced hepatocellular carcinoma treated with sorafenib
Haitao Yu,
Ganglian Lin,
Junyan Jiang,
Jiangqiao Yao,
Zhenyan Pan,
Haonan Xie,
Zhiyuan Bo,
Qikuan He,
Jinhuan Yang,
Ziyan Chen,
Jiacheng Li,
Yi Wang,
Zhengping Yu,
Yehuda G. Assaraf,
Gang Chen
Affiliations
Haitao Yu
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Ganglian Lin
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Junyan Jiang
Alberta Institute, Wenzhou Medical University, Wenzhou, Zhejiang, China
Jiangqiao Yao
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Zhenyan Pan
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Haonan Xie
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Zhiyuan Bo
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Qikuan He
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Jinhuan Yang
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Ziyan Chen
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Jiacheng Li
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Yi Wang
Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang, China
Zhengping Yu
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Yehuda G. Assaraf
The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel
Gang Chen
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
The gut microbiota plays an important role in the development and treatment of hepatocellular carcinoma (HCC). However, the implication of specific gut microbiota in targeted sorafenib therapy for advanced HCC and the microbiota mode of action, remain to be elucidated. Here, we confirmed that four bacterial genera, Lachnoclostridium, Lachnospira, Enterobacter and Enterococcus, are associated with the therapeutic efficacy of Sorafenib, and that Enterobacter faecium (Efm) plays a crucial role in modulating the sorafenib activity. The effective colonization by Emf induced the IL-12 and IFN-γ production and an increased proportion of IFN-γ+CD8+ T cells in the tumor microenvironment. Finally, exopolysaccharides (EPS) from Efm were the primary inducer to prompt IFN-γ+CD8+ T cells to secrete IFN-γ, which together with sorafenib instigated ferroptosis in HCC cells. Collectively, these results indicate that Efm is a promising probiotics that enhances the efficacy of sorafenib treatment in advanced HCC.
