Synergistic activity of Enterococcus Faeciu m-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

doi:10.1080/19490976.2024.2410474

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. Epub 2024 Oct 1.

Authors

Haitao Yu^{1

2

3}, Ganglian Lin^{1

2

3}, Junyan Jiang⁴, 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 Wang⁵, Zhengping Yu¹, Yehuda G Assaraf⁶, 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.

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.

MeSH terms

Animals
Antineoplastic Agents / pharmacology
CD8-Positive T-Lymphocytes* / immunology
Carcinoma, Hepatocellular* / drug therapy
Carcinoma, Hepatocellular* / immunology
Carcinoma, Hepatocellular* / microbiology
Cell Line, Tumor
Enterococcus faecium* / drug effects
Ferroptosis* / drug effects
Gastrointestinal Microbiome / drug effects
Humans
Interferon-gamma* / immunology
Interferon-gamma* / metabolism
Liver Neoplasms* / drug therapy
Liver Neoplasms* / immunology
Liver Neoplasms* / microbiology
Male
Mice
Probiotics / pharmacology
Sorafenib* / pharmacology
Sorafenib* / therapeutic use
Tumor Microenvironment / drug effects

Substances

Sorafenib
Interferon-gamma
Antineoplastic Agents

Grants and funding

The work was supported by the National Natural Science Foundation of China [81703310, 81703310 and 81772628]; the National College Students Innovation Entrepreneurship Training Program [202110343054X]; the Research Foundation of National Health Commission of China- Major Medical and Health Technology Project for Zhejiang Province [WKJ-ZJ-1706]; Science and Technology Plan Project of Wenzhou Municipality [Y2020153].