Basic Study
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World J Gastrointest Oncol. Jan 15, 2025; 17(1): 97831
Published online Jan 15, 2025. doi: 10.4251/wjgo.v17.i1.97831
Interleukin-17A facilitates tumor progression via upregulating programmed death ligand-1 expression in hepatocellular carcinoma
Zhong-Xia Yang, Li-Ting Zhang, Xiao-Jun Liu, Xue-Bin Peng, Xiao-Rong Mao
Zhong-Xia Yang, Li-Ting Zhang, Xiao-Rong Mao, The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, Gansu Province, China
Zhong-Xia Yang, Xue-Bin Peng, Xiao-Rong Mao, Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
Xiao-Jun Liu, Department of Radiotherapy, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
Author contributions: Yang ZX, Zhang LT, and Mao XR designed the research study; Yang ZX and Peng XB performed the research; Yang ZX and Liu XJ analyzed the data and wrote the manuscript; Zhang LT and Mao XR critically revised the article.
Supported by the Natural Science Foundation of Gansu Province, No. 21JR7RA373 and No. 24JRRA295.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of the First Hospital of Lanzhou University, No. LDYYLL2021-319 and No. LDYYLL2024-457.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Animal Experimental Ethical Inspection of Gansu University of Chinese Medicine, No. SY2023-766.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xiao-Rong Mao, Doctor, Chief Physician, Department of Infectious Diseases, The First Hospital of Lanzhou University, No. 1 Donggangxi Road, Chengguan District, Lanzhou 730000, Gansu Province, China. layygrk@126.com
Received: June 10, 2024
Revised: September 2, 2024
Accepted: October 28, 2024
Published online: January 15, 2025
Processing time: 184 Days and 20.5 Hours
Abstract
BACKGROUND

Hepatocellular carcinoma (HCC) is an inflammation-associated tumor with a dismal prognosis. Immunotherapy has become an important treatment strategy for HCC, as immunity is closely related to inflammation in the tumor microenvironment. Inflammation regulates the expression of programmed death ligand-1 (PD-L1) in the immunosuppressive tumor microenvironment and affects immunotherapy efficacy. Interleukin-17A (IL-17A) is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different tumors. We hypothesized that IL-17A participates in tumor progression by affecting the level of immune checkpoint molecules in HCC.

AIM

To investigate the effect and mechanism of action of IL-17A on PD-L1 expression and to identify attractive candidates for the treatment of HCC.

METHODS

The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR, western blotting, and flow cytometry. Mechanistic studies were conducted with gene knockout models and pathway inhibitors. The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells. The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro, and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo.

RESULTS

IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner, whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A. IL-17A enhanced the survival of HCC cells in the coculture system. IL-17A increased the viability, G2/M ratio, and migration of HCC cells and decreased the apoptotic index. Cyclin D1, VEGF, MMP9, and Bcl-1 expression increased after IL-17A treatment, whereas BAX expression decreased. The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8 + T lymphocyte infiltration in an HCC mouse model.

CONCLUSION

IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapentaplegic 2 signaling pathway in HCC cells. Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo.

Keywords: Interleukin-17A; Programmed death ligand-1; Interleukin-17A receptor; Small mothers against decapentaplegic 2; Hepatocellular carcinoma; Immunotherapy

Core Tip: Overexpression of programmed death ligand-1 (PD-L1) on tumor cells promotes cancer immune escape through inhibiting T cell function. Interleukin-17A (IL-17A) can increase the expression of PD-L1 in tumor cells and promote tumor progression. However, related research in hepatocellular carcinoma (HCC) is scarce. We clarified a novel mechanism by which IL-17A upregulated PD-L1 expression in HCC cells by the IL-17A receptor/phosphorylation-small mothers against decapentaplegic 2 axis. IL-17A could drive immune escape and promote proliferation, migration, and angiogenesis of HCC cells while inhibiting the apoptosis of HCC cells. IL-17A inhibition enhanced the therapeutic efficacy of the PD-L1 antibody in HCC in vivo.