Shen ZH, Luo WW, Ren XC, Wang XY, Yang JM. Expression of nucleus accumbens-1 in colon cancer negatively modulates antitumor immunity. World J Gastrointest Oncol 2022; 14(12): 2329-2339 [PMID: 36568940 DOI: 10.4251/wjgo.v14.i12.2329]
Corresponding Author of This Article
Jin-Ming Yang, Doctor, Academic Editor, Department of Cancer Biology and Toxicology, University of Kentucky College of Medicine, 101 Main Building Lexington, MA 40506, United States. yangjinming285@sina.com
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Medicine, General & Internal
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Basic Study
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Dec 15, 2022 (publication date) through Mar 1, 2026
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World Journal of Gastrointestinal Oncology
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1948-5204
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Shen ZH, Luo WW, Ren XC, Wang XY, Yang JM. Expression of nucleus accumbens-1 in colon cancer negatively modulates antitumor immunity. World J Gastrointest Oncol 2022; 14(12): 2329-2339 [PMID: 36568940 DOI: 10.4251/wjgo.v14.i12.2329]
World J Gastrointest Oncol. Dec 15, 2022; 14(12): 2329-2339 Published online Dec 15, 2022. doi: 10.4251/wjgo.v14.i12.2329
Expression of nucleus accumbens-1 in colon cancer negatively modulates antitumor immunity
Zhao-Hua Shen, Wei-Wei Luo, Xing-Cong Ren, Xiao-Yan Wang, Jin-Ming Yang
Zhao-Hua Shen, Wei-Wei Luo, Xiao-Yan Wang, Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
Xing-Cong Ren, Jin-Ming Yang, Department of Cancer Biology and Toxicology, University of Kentucky College of Medicine, Lexington, MA 40506, United States
Author contributions: Yang JM and Wang XY supervised the project and revised the manuscript; Shen ZH performed the in vitro and in vivo experiments, generated the figures, and revised the manuscript; Luo WW completed the analysis of the results; Ren XC contributed to the study design.
Supported bythe Changsha Municipal Natural Science Foundation, No. kq2014258.
Institutional review board statement: The study was reviewed and approved by the IRB of Third Xiangya Hospital, Central South University (Approval No. 2020-S195).
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the IRB of Third Xiangya Hospital, Central South University (No. 2020-S298).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors declare that there are no conflicts of interest.
Data sharing statement: Data can be acquired from the corresponding author.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Corresponding author: Jin-Ming Yang, Doctor, Academic Editor, Department of Cancer Biology and Toxicology, University of Kentucky College of Medicine, 101 Main Building Lexington, MA 40506, United States. yangjinming285@sina.com
Received: July 10, 2022 Peer-review started: July 10, 2022 First decision: September 26, 2022 Revised: October 16, 2022 Accepted: November 21, 2022 Article in press: November 21, 2022 Published online: December 15, 2022 Processing time: 154 Days and 24 Hours
Abstract
BACKGROUND
Nucleus accumbens-1 (NAC-1) is highly expressed in a variety of tumors, including colon cancer, and is closely associated with tumor recurrence, metastasis, and invasion.
AIM
To determine whether and how NAC-1 affects antitumor immunity in colon cancer.
METHODS
NAC-1-siRNA was transfected into RKO colon cancer cells to knock down NAC expression; tumor cells with or without knockdown of NAC-1 were treated with CD8+ T cells to test their cytocidal effect. The level of the immune checkpoint programmed death receptor-1 ligand (PD-L1) in colon cancer cells with or without knockdown of NAC-1 was analyzed using Quantitative real-time polymerase chain reaction and Western blotting. A double luciferase reporter assay was used to examine the effects of NAC-1 on the transcription of PD-L1. Mice bearing MC-38-OVA colon cancer cells expressing NAC-shRNA or control-shRNA were treated with OT-I mouse CD8+ T cells to determine the tumor response to immunotherapy. Immune cells in the tumor tissues were analyzed using flow cytometry. NAC-1, PD-L1 and CD8+ T cells in colon cancer specimens from patients were examined using immunohistochemistry staining.
RESULTS
Knockdown of NAC-1 expression in colon cancer cells significantly enhanced the cytocidal effect of CD8+ T cells in cell culture experiments. The sensitizing effect of NAC-1 knockdown on the antitumor action of cytotoxic CD8+ T cells was recapitulated in a colon cancer xenograft animal model. Furthermore, knockdown of NAC-1 in colon cancer cells decreased the expression of PD-L1 at both the mRNA and protein levels, and this effect could be rescued by transfection of an RNAi-resistant NAC-1 expression plasmid. In a reporter gene assay, transient expression of NAC-1 in colon cancer cells increased the promoter activity of PD-L1, indicating that NAC-1 regulates PD-L1 expression at the transcriptional level. In addition, depletion of tumoral NAC-1 increased the number of CD8+ T cells but decreased the number of suppressive myeloid-derived suppressor cells and regulatory T cells.
CONCLUSION
Tumor expression of NAC-1 is a negative determinant of immunotherapy.
Core Tip: We determined whether and how nucleus accumbens-1 (NAC-1) affects antitumor immunity in colon cancer. Knockdown of NAC-1 expression in colon cancer cells significantly enhanced the cytocidal effect of CD8+ T cells. Knockdown of NAC-1 in colon cancer cells decreased the expression of programmed death receptor-1 ligand. Depletion of tumoral NAC-1 increased the amount of CD8+ T cells but decreased the amount of suppressive myeloid-derived suppressor cells and regulatory T cells. It comes to a conclusion that tumoral expression of NAC-1 is a negative determinant of immunotherapy.
