Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Dec 15, 2023; 15(12): 2138-2149
Published online Dec 15, 2023. doi: 10.4251/wjgo.v15.i12.2138
Combined TIM-3 and PD-1 blockade restrains hepatocellular carcinoma development by facilitating CD4+ and CD8+ T cell-mediated antitumor immune responses
Xu-Sheng Zhang, Hong-Cai Zhou, Peng Wei, Long Chen, Wei-Hu Ma, Lin Ding, Shi-Cai Liang, Ben-Dong Chen
Xu-Sheng Zhang, Hong-Cai Zhou, Peng Wei, Long Chen, Wei-Hu Ma, Lin Ding, Shi-Cai Liang, School of Clinical Medicine, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
Ben-Dong Chen, Department of Hepatobiliary Surgery, The General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
Ben-Dong Chen, Hepatobiliary Pancreatic Surgical, Ningxia Hepatobiliary Pancreatic Surgical Diseases Clinical Research Center, Yinchuan 750004, Ningxia Hui Autonomous Region, China
Co-first authors: Xu-Sheng Zhang and Peng Wei.
Author contributions: Zhang XS, Wei P, and Liang SC were responsible for research design; Zhou HC, Peng Wei, and Long Chen contributed to the conducting the experiments; Zhang XS, Ding L, Chen BD, and Liang SC involved in the data acquisition; Chen L, Ma WH, and Ding L participated in the data analysis; Zhou HC, Ma WH, and Chen BD wrote the manuscript; and all the authors have contributed to the completion of this paper.
Supported by the First-Class Discipline Construction Founded Project of Ningxia Medical University and the School of Clinical Medicine, No. 2020008.
Institutional review board statement: This study was conducted with the approval of the Ethics Committee of the General Hospital of Ningxia Medical University. All participants provided clinical specimens and signed the informed consent forms.
Institutional animal care and use committee statement: All animal care and experimental procedures were approved by the Ethics Committee of the General Hospital of Ningxia Medical University.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: All the data obtained in the current study were available from the corresponding authors on reasonable request.
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: Ben-Dong Chen, MD, Doctor, Department of Hepatobiliary Surgery, The General Hospital of Ningxia Medical University, No. 804 Shengli Street, Yinchuan 750004, Ningxia Hui Autonomous Region, China. bendong8511@nyfy.com.cn
Received: September 5, 2023
Peer-review started: September 5, 2023
First decision: September 15, 2023
Revised: October 9, 2023
Accepted: November 8, 2023
Article in press: November 8, 2023
Published online: December 15, 2023
Processing time: 99 Days and 20.6 Hours
ARTICLE HIGHLIGHTS
Research background

Hepatocellular carcinoma (HCC) is the fourth intractable tumors in clinic worldwide. Recently, immune checkpoint inhibitors (ICIs), a novel immune therapy, has been identified as an efficient and safe therapy for malignant tumors, which have attracted more attention and give novel directions for HCC treatment.

Research motivation

ICIs targeting programmed cell death protein 1 (PD-1) and T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) are benefit to the resume of anti-tumor immunity response and hold extreme potential as efficient therapies for certain malignancies. Given the complex pathological mechanisms of HCC, ICIs with a single target exhibit poor overall response rate in HCC patients. Therefore, it’s of great significance to identify more effective immunotherapies and provide more treatment options to achieve gratifying survival rate and prognosis for HCC patients.

Research objectives

This study investigated the effects of combined TIM-3 and PD-1 blockade on tumor development in an HCC mouse model, aiming to identify more effective immunotherapies and provide more treatment options for HCC patients.

Research methods

We first detected the levels of PD-1 CD4+, PD-1 CD8+, TIM-3 CD4+, and TIM-3 CD8+ in tumor tissues, ascites, and matched adjacent tissues from HCC patients. Next, we investigated the effects of combined and individual blockage of TIM-3 and PD-1 on an HCC xenograft mouse model. Tumor growth and CD4+ and CD8+ T cell-mediated antitumor immune responses were assessed.

Research results

PD-1 and TIM-3 expression was upregulated in CD4+ and CD8+ T cells isolated from tumor tissues and ascites of HCC patients. TIM-3 mAb and PD-1 mAb treatment both reduced tumor volume and weight, while combined blockade had more substantial anti-tumor effects compared with individual treatment. The combined therapy increased T cell infiltration into tumor tissues, and ameliorated CD4+ and CD8+ T cell exhaustion in HCC mouse model.

Research conclusions

Combined TIM-3 and PD-1 blockage has more substantial anti-tumor effects compared with individual blockage. Combined TIM-3 and PD-1 blockage restrains HCC development by facilitating CD4+ and CD8+ T cell-mediated antitumor immune responses.

Research perspectives

We need to explore the effects of combination of multiple ICIs to provide better options for HCC treatment.