Synergistic activity of Enterococcus Faeciu m-induced ferroptosis via expansion of IFN-γ+CD8+ T cell population in advanced hepatocellular carcinoma treated with sorafenib

  • Gut Microbes. 2024 Jan-Dec;16(1):2410474. doi: 10.1080/19490976.2024.2410474.
Haitao Yu  1  2  3 ,  Ganglian Lin  1  2  3 ,  Junyan Jiang  4 ,  Jiangqiao Yao  1  2  3 ,  Zhenyan Pan  1  2  3 ,  Haonan Xie  1  2  3 ,  Zhiyuan Bo  1  2  3 ,  Qikuan He  1  2  3 ,  Jinhuan Yang  1  2  3 ,  Ziyan Chen  1  2  3 ,  Jiacheng Li  1  2  3 ,  Yi Wang  5 ,  Zhengping Yu  1 ,  Yehuda G Assaraf  6 ,  Gang Chen  1  2  3
Affiliations
  • 1. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 2. Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 3. Zhejiang-Germany Interdisciplinary Joint Laboratory of Hepatobiliary-Pancreatic Tumor and Bioengineering, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 4. Alberta Institute, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 5. Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 6. The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
PMID: 39353096 DOI: 10.1080/19490976.2024.2410474
Abstract

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.

Keywords
Hepatocellular carcinoma; IFN-γ+CD8+ T cell; ferroptosis; gut microbiota; sorafenib.
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