Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 14, 2020; 26(26): 3737-3749
Published online Jul 14, 2020. doi: 10.3748/wjg.v26.i26.3737
Combining protein arginine methyltransferase inhibitor and anti-programmed death-ligand-1 inhibits pancreatic cancer progression
Nan-Nan Zheng, Min Zhou, Fang Sun, Man-Xiu Huai, Yi Zhang, Chun-Ying Qu, Feng Shen, Lei-Ming Xu
Nan-Nan Zheng, Min Zhou, Fang Sun, Man-Xiu Huai, Yi Zhang, Chun-Ying Qu, Feng Shen, Lei-Ming Xu, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
Author contributions: Zheng NN and Zhou M contributed equally to this work; Zheng NN and Zhou M performed the majority of the experiments and wrote the paper; Sun F and Huai MX analyzed the data; Zhang Y, Qu CY, and Shen F edited the manuscript; Xu LM designed and supervised the study; all authors have read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81472844.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine.
Institutional animal care and use committee statement: This study was reviewed and approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (XHEC-F- 2018-062).
Conflict-of-interest statement: The authors declare that there are no conflicts of interest related to this study.
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: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Lei-Ming Xu, MD, PhD, Chief Doctor, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Yangpu District, Shanghai 200092, China. xuleiming@xinhuamed.com.cn
Received: January 19, 2020
Peer-review started: January 19, 2020
First decision: May 1, 2019
Revised: June 2, 2020
Accepted: June 20, 2020
Article in press: June 20, 2020
Published online: July 14, 2020
Processing time: 177 Days and 4.5 Hours
ARTICLE HIGHLIGHTS
Research background

The mechanism underlying pancreatic cancer resistance to anti-programmed death-1 (PD-1)/programmed death-ligand-1 (PD-L1) immunotherapy is poorly understood, but it has been suggested that PD-L1 expression in tumors is an important indicator of checkpoint immunotherapy efficacy. Considered an epigenetic molecular marker, protein arginine methyltransferases (PRMT)1 is the predominant type I methyltransferase responsible for the majority of cellular arginine methylation events. PRMT1 is deregulated in a wide variety of cancer types, whose biological role in tumor immunity is undefined.

Research motivation

We hope to search for new small-molecule inhibitors that influence PD-L1 expression and affect the efficacy of immunotherapy in pancreatic cancer.

Research objectives

To explore the combined antitumor effects of anti-PD-L1 and type I PRMT inhibitor on pancreatic cancer and the underlying mechanisms in vivo.

Research methods

The murine pancreatic ductal adenocarcinoma (PDAC) cells Panc02 were implanted subcutaneously in C57BL/6 mice, and the tumor-bearing mice were used to assess the drug efficacy, toxic and side effects, and tumor growth in vivo. We determined the expression of key immune checkpoint proteins, detected the apoptosis in tumor tissues, and analyzed the immune cells by flow cytometry (FCM). Immunohistochemistry staining for Ki67, TUNEL assay, and PRMT1/PD-L1 immunofluorescence were exploited to elucidate the underlying molecular mechanism.

Research results

Cultured Panc02 cells did not express PD-L1 in vitro, but tumor cells derived from Panc02 transplanted tumors expressed PD-L1. Drug treatment had no obvious toxic and side effects on mice. Neither PT1001B nor anti-PD-L1 mAb alone inhibited tumor growth compared to the control. However, the therapeutic efficacy of anti-PD-L1 mAb was significantly enhanced by the addition of PT1001B. PT1001B improved antitumor immunity by inhibiting PD-L1 expression on tumor cells, upregulating tumor-infiltrating CD8+ T lymphocytes, and decreasing PD-1+ leukocytes. In addition, PT1001B amplified the inhibitory effect of anti-PD-L1 mAb in inhibiting proliferation and promoting apoptosis of tumor cells. In tumor tissues, the downregulation of PRMT1 was related to the downregulation of PD-L1.

Research conclusions

PT1001B enhances anti-tumor immunity and combining it with anti-PD-L1 inhibits tumor growth effectively, reversing the resistance of PDAC to immunotherapy.

Research perspectives

Our data demonstrate that PT1001B is a promising inhibitor to change the tumor microenvironment in pancreatic cancer. PRMT1 is a potential therapeutic target, and additional research aimed at elucidating the mechanisms by which PRMT1 regulates PD-L1 is warranted.