Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. May 15, 2024; 16(5): 2113-2122
Published online May 15, 2024. doi: 10.4251/wjgo.v16.i5.2113
Immunomodulation of adipose-derived mesenchymal stem cells on peripheral blood mononuclear cells in colorectal cancer patients with COVID-19
Jun-Feng Wang, Xiao-Xia Yang, Jian Zhang, Yan Zheng, Fu-Qing Zhang, Xiao-Feng Shi, Yu-Liang Wang
Jun-Feng Wang, Department of Colorectal Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
Xiao-Xia Yang, Department of Neurology, Tianjin First Center Hospital, Tianjin 300192, China
Jian Zhang, Prosthodontics Studio, Tianjin Stomatological Hospital, Tianjin 300041, China
Yan Zheng, Fu-Qing Zhang, Yu-Liang Wang, Department of Clinical Laboratory Medicine, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
Xiao-Feng Shi, Department of Emergency, Tianjin First Central Hospital, Tianjin 300192, China
Co-first authors: Jun-Feng Wang and Xiao-Xia Yang.
Co-corresponding authors: Xiao-Feng Shi and Yu-Liang Wang.
Author contributions: Wang JF, Yang XX, Zhang J, Zheng Y, and Wang YL performed the experiments; Wang JF, Yang XX, and Wang YL acquired and analyzed the data; Wang JF, Shi XF, and Wang YL interpreted the data; All authors approved the final version of the article. Wang YL and Shi XF conceived and designed the project and have played pivotal and indispensable roles in the experimental design, data interpretation, and manuscript preparation as co-corresponding authors; Zhang FQ drafted the manuscript; Wang YL wrote the manuscript, conceptualized, designed, and supervised the entire project process; conducted the literature research, revised the manuscript, and handled its submission; Shi XF made significant contributions by conducting data re-analysis and re-interpretation.
Supported by National Natural Science Foundation of China, No. 81470982.
Institutional review board statement: The institutional review board of Tianjin Medical University Cancer Hospital approved the study protocol. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent statement: Informed consent was obtained from all patients.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: All data generated or analyzed supporting conclusions are included in the current 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: Yu-Liang Wang, MD, PhD, Director, Department of Clinical Laboratory Medicine, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, No. 22 Pingjiang Road, Hexi Distinct, Tianjin 300211, China. wang_yu_l@163.com
Received: January 2, 2024
Peer-review started: January 2, 2024
First decision: January 10, 2024
Revised: January 19, 2024
Accepted: March 7, 2024
Article in press: March 7, 2024
Published online: May 15, 2024
Processing time: 128 Days and 3.1 Hours
Abstract
BACKGROUND

Accumulating evidence has shown that adipose tissue-derived mesenchymal stem cells (ADSCs) are an effective therapeutic approach for managing coronavirus disease 2019 (COVID-19); however, further elucidation is required to determine their underlying immunomodulatory effect on the mRNA expression of T helper cell-related transcription factors (TFs) and cytokine release in peripheral blood mononuclear cells (PBMCs).

AIM

To investigate the impact of ADSCs on the mRNA expression of TFs and cytokine release in PBMCs from colorectal cancer (CRC) patients with severe COVID-19 (CRC+ patients).

METHODS

PBMCs from CRC+ patients (PBMCs-C+) and age-matched CRC patients (PBMCs-C) were stimulated and cultured in the presence/absence of ADSCs. The mRNA levels of T-box TF TBX21 (T-bet), GATA binding protein 3 (GATA-3), RAR-related orphan receptor C (RORC), and forkhead box P3 (FoxP3) in the PBMCs were determined by reverse transcriptase-polymerase chain reaction. Culture supernatants were evaluated for levels of interferon gamma (IFN-γ), interleukin 4 (IL-4), IL-17A, and transforming growth factor beta 1 (TGF-β1) using an enzyme-linked immunosorbent assay.

RESULTS

Compared with PBMCs-C, PBMCs-C+ exhibited higher mRNA levels of T-bet and RORC, and increased levels of IFN-γ and IL-17A. Additionally, a significant decrease in FoxP3 mRNA and TGF-β1, as well as an increase in T-bet/GATA-3, RORC/FoxP3, IFN-γ/IL-4, and IL-17A/TGF-β1 ratios were observed in PBMCs-C+. Furthermore, ADSCs significantly induced a functional regulatory T cell (Treg) subset, as evidenced by an increase in FoxP3 mRNA and TGF-β1 release levels. This was accompanied by a significant decrease in the mRNA levels of T-bet and RORC, release of IFN-γ and IL-17A, and T-bet/GATA-3, RORC/FoxP3, IFN-γ/IL-4, and IL-17A/TGF-β1 ratios, compared with the PBMCs-C+alone.

CONCLUSION

The present in vitro studies showed that ADSCs contributed to the immunosuppressive effects on PBMCs-C+, favoring Treg responses. Thus, ADSC-based cell therapy could be a beneficial approach for patients with severe COVID-19 who fail to respond to conventional therapies.

Keywords: Colorectal cancer; COVID-19; Adipose-derived mesenchymal stem cells; T helper cell; Immunomodulation

Core Tip: In patients with colorectal cancer (CRC) who develop severe coronavirus disease 2019, peripheral blood mononuclear cells display a severe pro-inflammatory phenotype and corresponding functional cytokine profile upon deliberate in vitro stimulation. Adipose tissue-derived mesenchymal stem cells (ADSCs) can significantly induce a regulatory T cell-biased immunosuppressive response while concurrently restraining exaggerated T helper 1 (Th1)-predominant and Th17 pro-inflammatory responses. These results indicate the protective immunomodulatory activity of proactive ADSC therapy by manipulating Th cell polarization to create an anti-inflammatory environment against severe acute respiratory syndrome coronavirus 2-induced severe hyperinflammatory responses.