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  3. Sorafenib Promotes Treg Cell Differentiation To Compromise Its Efficacy via VEGFR/AKT/Foxo1 Signaling in Hepatocellular Carcinoma

Sorafenib Promotes Treg Cell Differentiation To Compromise Its Efficacy via VEGFR/AKT/Foxo1 Signaling in Hepatocellular Carcinoma

  • Cell Mol Gastroenterol Hepatol. 2024 Dec 30:101454. doi: 10.1016/j.jcmgh.2024.101454.
Yingying Shen 1,  Hanliang Wang 1,  Zeyu Ma 2,  Minyan Hao 1,  Shuowang Wang 1,  Junwei Li 1,  Yue Fang 3,  Lei Yu 1,  Yingying Huang 4,  Changrong Wang 5,  Jingjing Xiang 5,  Zhijian Cai 3,  Jianli Wang 6,  Hongchuan Jin 1,  Jia Zhou 7,  Jufeng Guo 8,  Pingting Ying 9,  Xian Wang 10
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang, China.
  • 2 Department of Dermatology and Venerology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang, China.
  • 3 Institute of Immunology and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 4 Core Facilities, School of Medicine Zhejiang University, Hangzhou, China.
  • 5 Department of Pathology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, China.
  • 6 Institute of Immunology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, China.
  • 7 Department of Medical Oncology, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: zhoujia90@zju.edu.cn.
  • 8 Department of Breast Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, China. Electronic address: 21118181@zju.edu.cn.
  • 9 Department of Medical Oncology, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: yingpt@zju.edu.cn.
  • 10 Department of Medical Oncology, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: wangx118@zju.edu.cn.
PMID: 39743020 DOI: 10.1016/j.jcmgh.2024.101454
Abstract

Background & aims: Sora is the first-line drug for advanced hepatocellular carcinoma (HCC). However, acquired resistance to Sora treatment largely hinders its therapeutic efficacy, and the mechanisms underlying Sora resistance remain poorly understood. Here, we revealed a new mechanism by which Sora promotes the differentiation of regulatory T (Treg) cells to suppress the immune response in the HCC tumor microenvironment (TME) and induce Sora resistance.

Methods: Human liver tissues were obtained from HCC patients. Female C57BL/6J, OT-II, and Foxp3GFP mice were also used. Flow cytometry was used to analyze immune cells in TME. Flow cytometry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay were performed to evaluate Treg cell differentiation. Immunoblotting was conducted to identify relevant proteins. Mouse and human tumor tissues were evaluated via multiplex immunofluorescence staining. Sora-treated HCC tissues and Sora-treated Treg cells were subjected to RNA Sequencing analysis. Tumor models were generated and treated with Sora, Sora combined with an anti-CD25 antibody, or Sora combined with the Foxo1 inhibitor AS1842856.

Results: First, we found through bioinformatic analysis that Sora suppresses the immune response in HCC. Furthermore, Sora increased the Treg cell population to promote the formation of an immunosuppressive TME in HCC. In vitro, Sora promoted Treg cell differentiation and increased the immunosuppressive activity of Treg cells. Activating VEGF and Akt abolished the effect of Sora on Treg cell differentiation, whereas inhibiting Foxo1 compromised Sora-induced Treg cell differentiation, indicating that the induction of Treg cells by Sora is dependent on the VEGFR/Akt/Foxo1 pathway. Finally, Treg inactivation by an anti-CD25 antibody or the Foxo1 inhibitor AS1842856 in combination with Sora showed greater efficacy in the treatment of HCC.

Conclusions: Sora induced Treg cell differentiation by inhibiting VEGFR/Akt signaling and activating Foxo1, thus suppressing the immune response and reducing Sora efficacy. Treg inactivation might be a promising strategy to alleviate the immunosuppressive TME and overcome Sora resistance.

Keywords

Foxo1; Hepatocellular Carcinoma; Immunosuppression; Sora Resistance; Treg Cells.

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