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World J Gastroenterol. May 14, 2022; 28(18): 1934-1945
Published online May 14, 2022. doi: 10.3748/wjg.v28.i18.1934
Targeting pancreatic cancer immune evasion by inhibiting histone deacetylases
Wynne Sim, Wei-Meng Lim, Ling-Wei Hii, Chee-Onn Leong, Chun-Wai Mai
Wynne Sim, School of Medicine, International Medical University, Kuala Lumpur 57000, Malaysia
Wei-Meng Lim, Ling-Wei Hii, School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia
Wei-Meng Lim, Ling-Wei Hii, Chee-Onn Leong, Center for Cancer and Stem Cell Research, Institute for Research, Development, and Innovation, International Medical University, Kuala Lumpur 57000, Malaysia
Chee-Onn Leong, AGTC Genomics, Kuala Lumpur 57000, Malaysia
Chun-Wai Mai, State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
Chun-Wai Mai, Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
Author contributions: Sim W provided the first draft; Sim W, Lim WM and Hii LW prepared the figures and tables; Sim W, Lim WM, Hii LW, Leong CO, Mai CW wrote and finalized the manuscript; Lim WM and Mai CW designed the outline and coordinated the writing of the paper.
Supported by International Medical University to Sim W, Lim WM, and Leong CO, No. BMS I/2020(10); Shanghai Municipal Science and Technology Commission to Mai CW, No. 20WZ250460.
Conflict-of-interest statement: There is no conflict of interest with any authors contributed to this manuscript.
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: Chun-Wai Mai, BPharm, PhD, Postdoctoral Fellow, State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pujian Road, Building No. 17, Pudong New District, Shanghai 200127, China. mai.chunwai@outlook.com
Received: January 7, 2022
Peer-review started: January 7, 2022
First decision: March 9, 2022
Revised: March 17, 2022
Accepted: April 4, 2022
Article in press: April 4, 2022
Published online: May 14, 2022
Processing time: 124 Days and 19.9 Hours
Abstract

The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development. Regardless, it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses, thus allowing continuous tumor growth and development. Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer. Compared with other cancers, pancreatic cancer has a tumor microenvironment that can resist most treatment modalities, including emerging immunotherapy. Sadly, the use of immunotherapy has yet to bring significant clinical breakthrough among pancreatic cancer patients, suggesting that pancreatic cancer has successfully evaded immunomodulation. In this review, we summarize the impact of genetic alteration and epigenetic modification (especially histone deacetylases, HDAC) on immune evasion in pancreatic cancer. HDAC overexpression significantly suppresses tumor suppressor genes, contributing to tumor growth and progression. We review the evidence on HDAC inhibitors in tumor eradication, improving T cells activation, restoring tumor immunogenicity, and modulating programmed death 1 interaction. We provide our perspective in targeting HDAC as a strategy to reverse immune evasion in pancreatic cancer.

Keywords: Histone acetylation; Histone deacetylases inhibitors; Immune evasion; Pancreatic cancers; Pancreatic ductal adenocarcinoma

Core Tip: There are several broad reviews covering histone deacetylases (HDAC) in cancer but none on its role in modulating immune evasion in pancreatic cancer. This is the first review to discuss the role of HDAC in the context of immune-evading pancreatic cancer. We also summarize the evidence of HDAC inhibitors in targeting immune-evading pancreatic cancer. This mini review also covers our perspective in the strategies to target overexpression of HDAC in pancreatic cancer.