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World J Gastroenterol. Jul 21, 2022; 28(27): 3346-3358
Published online Jul 21, 2022. doi: 10.3748/wjg.v28.i27.3346
Regulatory T cells and their associated factors in hepatocellular carcinoma development and therapy
Chun-Ye Zhang, Shuai Liu, Ming Yang
Chun-Ye Zhang, Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, United States
Shuai Liu, The First Affiliated Hospital, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
Ming Yang, Department of Surgery, University of Missouri, Columbia, MO 65211, United States
Author contributions: Zhang CY, Liu S, and Yang M designed and collected data, wrote, revised, and finalized the manuscript; all authors contributed equally, and shared the first authorship.
Conflict-of-interest statement: There are no conflicts of interest to report.
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: Ming Yang, DVM, PhD, Postdoctoral Fellow, Department of Surgery, University of Missouri, Room 2203, NexGen Precision Building, 1030 Hitt Street, Columbia, MO 65211, United States. yangmin@health.missouri.edu
Received: January 3, 2022
Peer-review started: January 3, 2022
First decision: January 23, 2022
Revised: January 27, 2022
Accepted: June 23, 2022
Article in press: June 23, 2022
Published online: July 21, 2022
Processing time: 195 Days and 10.9 Hours
Abstract

Liver cancer is the third leading cause of cancer-related death worldwide with primary type hepatocellular carcinoma (HCC). Factors, including carcinogens, infection of hepatitis viruses, alcohol abuse, and non-alcoholic fatty liver disease (NAFLD), can induce HCC initiation and promote HCC progression. The prevalence of NAFLD accompanying the increased incidence of obesity and type 2 diabetes becomes the most increasing factor causing HCC worldwide. However, the benefit of current therapeutic options is still limited. Intrahepatic immunity plays critically important roles in HCC initiation, development, and progression. Regulatory T cells (Tregs) and their associated factors such as metabolites and secreting cytokines mediate the immune tolerance of the tumor microenvironment in HCC. Therefore, targeting Tregs and blocking their mediated factors may prevent HCC progression. This review summarizes the functions of Tregs in HCC-inducing factors including alcoholic and NAFLD, liver fibrosis, cirrhosis, and viral infections. Overall, a better understanding of the role of Tregs in the development and progression of HCC provides treatment strategies for liver cancer treatment.

Keywords: Hepatocellular carcinoma; Regulatory T cells; Alcoholic fatty liver disease; Non-alcoholic fatty liver disease; Treatment; Clinical trials

Core Tip: Liver cancer is the third leading cause of cancer-related death worldwide. Hepatocellular carcinoma (HCC) is the primary type of liver cancer. Factors, including carcinogenic infection of hepatitis viruses, alcohol abuse, and non-alcoholic fatty liver disease (NAFLD), can induce HCC initiation and promote HCC progression. The prevalence of NAFLD accompanying the increased incidence of obesity and type 2 diabetes becomes the most increasing factor causing HCC worldwide. However, the benefit of current therapeutic options is still limited. Intrahepatic immunity plays critically important roles in HCC initiation, development, and progression. Regulatory T cells (Tregs) and their associated factors such as metabolites and secreting cytokines mediate the immune tolerance of the tumor microenvironment in HCC. Therefore, targeting Tregs and blocking their mediated factors may prevent HCC progression. A better understanding of the role of Tregs in intrahepatic immunity is helpful to develop novel HCC treatment options.