Regorafenib enhances anti-tumor efficacy of immune checkpoint inhibitor by regulating IFN-γ/NSDHL/SREBP1/TGF-β1 axis in hepatocellular carcinoma

Lulu Xie; Mingyu Liu; Mingyue Cai; Wensou Huang; Yongjian Guo; Licong Liang; Weiguo Cai; Jianxin Liu; Wei Liang; Yitong Tan; Miaoling Lai; Liteng Lin; Kangshun Zhu

Biomedicine & Pharmacotherapy (Mar 2023)

Regorafenib enhances anti-tumor efficacy of immune checkpoint inhibitor by regulating IFN-γ/NSDHL/SREBP1/TGF-β1 axis in hepatocellular carcinoma

Lulu Xie,
Mingyu Liu,
Mingyue Cai,
Wensou Huang,
Yongjian Guo,
Licong Liang,
Weiguo Cai,
Jianxin Liu,
Wei Liang,
Yitong Tan,
Miaoling Lai,
Liteng Lin,
Kangshun Zhu

Affiliations

Lulu Xie: Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Radiology Center, and Minimally Invasive and Interventional Cancer Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510260, China
Mingyu Liu: Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Radiology Center, and Minimally Invasive and Interventional Cancer Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510260, China
Mingyue Cai: Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Radiology Center, and Minimally Invasive and Interventional Cancer Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510260, China
Wensou Huang: Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Radiology Center, and Minimally Invasive and Interventional Cancer Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510260, China
Yongjian Guo: Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Radiology Center, and Minimally Invasive and Interventional Cancer Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510260, China
Licong Liang: Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Radiology Center, and Minimally Invasive and Interventional Cancer Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510260, China
Weiguo Cai: Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Radiology Center, and Minimally Invasive and Interventional Cancer Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510260, China
Jianxin Liu: Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Radiology Center, and Minimally Invasive and Interventional Cancer Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510260, China
Wei Liang: Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Radiology Center, and Minimally Invasive and Interventional Cancer Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510260, China
Yitong Tan: Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Radiology Center, and Minimally Invasive and Interventional Cancer Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510260, China
Miaoling Lai: Department of Pathology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510260, China
Liteng Lin: Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Radiology Center, and Minimally Invasive and Interventional Cancer Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510260, China; Corresponding authors.
Kangshun Zhu: Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Radiology Center, and Minimally Invasive and Interventional Cancer Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510260, China; Corresponding authors.

Journal volume & issue: Vol. 159
p. 114254

Abstract

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Immune checkpoint inhibitor (ICI) shows low response rate in hepatocellular carcinoma (HCC) but the mechanisms underlying ICI resistance remains unclear. Interferon-γ (IFN-γ) has been widely determined as a prototypical antitumor cytokine. However, growing studies suggest that IFN-γ also mediates immunosuppression to promote tumor progression. Herein, we explored whether ICI-induced IFN-γ could activate immunosuppressive TGF-β1 to mediate ICI resistance. We demonstrated that cholesterol biosynthetic enzyme, NSDHL, was decreased in HCC tissues and associated with poor clinical prognosis. ICI-induced IFN-γ decreased NSDHL to activate SREBP1, which promoted TGF-β1 production, reduced T cell toxicity and enhanced Tregs infiltration, leading to ICI resistance. We also found that novel tyrosine kinase inhibitor, regorafenib, significantly reverse the above immunosuppressive effects by regulating NSDHL/SREBP1/TGF-β1 axis, which strengthened the effects of regorafenib plus ICI therapy against HCC. Noteworthily, regorafenib plus ICI therapy was more effective in HCC patients with higher serum TGF-β1. In conclusion, IFN-γ induced TGF-β1 to mediate ICI resistance. Regorafenib promotes anti-tumor immune response of ICI by regulating IFN-γ/NSDHL/SREBP1/TGF-β1 axis. Serum TGF-β1 may serve as a biomarker for predicting efficacy of regorafenib plus ICI therapy in HCC.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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