ISG12a promotes immunotherapy of HBV-associated hepatocellular carcinoma through blocking TRIM21/AKT/β-catenin/PD-L1 axis

Rilin Deng; Renyun Tian; Xinran Li; Yan Xu; Yongqi Li; Xintao Wang; Huiyi Li; Luoling Wang; Biaoming Xu; Di Yang; Songqing Tang; Binbin Xue; Chaohui Zuo; Haizhen Zhu

doi:10.1016/j.isci.2024.109533

ISG12a promotes immunotherapy of HBV-associated hepatocellular carcinoma through blocking TRIM21/AKT/β-catenin/PD-L1 axis

iScience. 2024 Mar 19;27(4):109533. doi: 10.1016/j.isci.2024.109533. eCollection 2024 Apr 19.

Authors

Rilin Deng^{1

2

3}, Renyun Tian^{1

2}, Xinran Li¹, Yan Xu¹, Yongqi Li⁴, Xintao Wang¹, Huiyi Li^{1

2}, Luoling Wang¹, Biaoming Xu⁵, Di Yang¹, Songqing Tang¹, Binbin Xue^{1

2}, Chaohui Zuo⁵, Haizhen Zhu^{1

2}

Affiliations

¹ Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, Hunan, China.
² Key Laboratory of Tropical Translational Medicine of Ministry of Education, Department of Pathogen Biology, School of Basic Medicine and Life Science, Department of Clinical Laboratory of the Second Affiliated Hospital, The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, The Second Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou 571199, Hainan, China.
³ Hunan Normal University School of Medicine, Changsha 410013, Hunan, China.
⁴ Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130031, Jilin, China.
⁵ Department of Gastroduodenal and Pancreatic Surgery, Translational Medicine Joint Research Center of Liver Cancer, Laboratory of Digestive Oncology, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Clinical Research Center For Tumor of Pancreaticobiliary Duodenal Junction In Hunan Province, Changsha 410013, Hunan, China.

Abstract

Hepatitis B virus (HBV) infection generally elicits weak type-I interferon (IFN) immune response in hepatocytes, covering the regulatory effect of IFN-stimulated genes. In this study, low level of IFN-stimulated gene 12a (ISG12a) predicted malignant transformation and poor prognosis of HBV-associated hepatocellular carcinoma (HCC), whereas high level of ISG12a indicated active NK cell phenotypes. ISG12a interacts with TRIM21 to inhibit the phosphorylation activation of protein kinase B (PKB, also known as AKT) and β-catenin, suppressing PD-L1 expression to block PD-1/PD-L1 signaling, thereby enhancing the anticancer effect of NK cells. The suppression of PD-1-deficient NK-92 cells on HBV-associated tumors was independent of ISG12a expression, whereas the anticancer effect of PD-1-expressed NK-92 cells on HBV-associated tumors was enhanced by ISG12a and treatments of atezolizumab and nivolumab. Thus, tumor intrinsic ISG12a promotes the anticancer effect of NK cells by regulating PD-1/PD-L1 signaling, presenting the significant role of innate immunity in defending against HBV-associated HCC.

Keywords: Cancer; Immune response; Immunology; NK cells.