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Resveratrol exerts antitumor effects by downregulating CD8(+)CD122(+) Tregs in murine hepatocellular carcinoma

CD4(+)Foxp3(+) regulatory T cells (Tregs) in the tumor microenvironment restrain antitumor immunity, resulting in tumor aggression and poor survival in hepatocellular carcinoma (HCC). CD8(+)CD122(+) Tregs have been previously shown to be more potent in immunosuppression than are CD4(+)Foxp3(+) Tregs...

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Autores principales: Zhang, Qunfang, Huang, Haiding, Zheng, Fang, Liu, Huazhen, Qiu, Feifei, Chen, Yuchao, Liang, Chun-Ling, Dai, Zhenhua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588216/
https://www.ncbi.nlm.nih.gov/pubmed/33150044
http://dx.doi.org/10.1080/2162402X.2020.1829346
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author Zhang, Qunfang
Huang, Haiding
Zheng, Fang
Liu, Huazhen
Qiu, Feifei
Chen, Yuchao
Liang, Chun-Ling
Dai, Zhenhua
author_facet Zhang, Qunfang
Huang, Haiding
Zheng, Fang
Liu, Huazhen
Qiu, Feifei
Chen, Yuchao
Liang, Chun-Ling
Dai, Zhenhua
author_sort Zhang, Qunfang
collection PubMed
description CD4(+)Foxp3(+) regulatory T cells (Tregs) in the tumor microenvironment restrain antitumor immunity, resulting in tumor aggression and poor survival in hepatocellular carcinoma (HCC). CD8(+)CD122(+) Tregs have been previously shown to be more potent in immunosuppression than are CD4(+)Foxp3(+) Tregs. Previous studies have demonstrated that resveratrol exerts its anti-cancer effects by downregulating CD4(+)Foxp3(+) and M2-like macrophages, two key immunoregulatory cells that maintain the immunosuppressive tumor microenvironment. In this study, we found that resveratrol inhibited the tumor growth in a subcutaneous Hepa1-6 HCC model and decreased the frequency of CD8(+)CD122(+) Tregs in the tumor as well as lymph nodes and spleen of the tumor-bearing mice. It also increased the percentage of IFN-γ-expressing CD8(+) T cells in the tumor and peripheral lymphoid organs. The antitumor effects of resveratrol were partially reversed by the adoptive transfer of exogenous CD8(+)CD122(+) Tregs into the tumor-bearing mice. Meanwhile, resveratrol treatment downregulated immunosuppressive cytokines, including TGF-β1 and interleukin-10, in the tumor while elevating antitumor cytokines, TNF-α and IFN-γ. It also inhibited the activation of STAT3 signaling in the tumor. As expected, resveratrol reduced the percentage of M2-like macrophages in the mice. Importantly, resveratrol suppressed orthotopic H22 tumor growth and decreased the frequency of CD8(+)CD122(+) Tregs and M2-like macrophages in the tumor-bearing mice. Furthermore, our studies showed that resveratrol, at non-cytotoxic concentrations, inhibited CD8(+)CD122(+) Treg differentiation from CD8(+)CD122(−) T cells in vitro. Thus, our studies unveiled a new immune mechanism underlying the immunosuppressive tumor microenvironment and demonstrated that resveratrol could help reverse it by diminishing CD8(+)CD122(+) Tregs.
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spelling pubmed-75882162020-11-03 Resveratrol exerts antitumor effects by downregulating CD8(+)CD122(+) Tregs in murine hepatocellular carcinoma Zhang, Qunfang Huang, Haiding Zheng, Fang Liu, Huazhen Qiu, Feifei Chen, Yuchao Liang, Chun-Ling Dai, Zhenhua Oncoimmunology Original Research CD4(+)Foxp3(+) regulatory T cells (Tregs) in the tumor microenvironment restrain antitumor immunity, resulting in tumor aggression and poor survival in hepatocellular carcinoma (HCC). CD8(+)CD122(+) Tregs have been previously shown to be more potent in immunosuppression than are CD4(+)Foxp3(+) Tregs. Previous studies have demonstrated that resveratrol exerts its anti-cancer effects by downregulating CD4(+)Foxp3(+) and M2-like macrophages, two key immunoregulatory cells that maintain the immunosuppressive tumor microenvironment. In this study, we found that resveratrol inhibited the tumor growth in a subcutaneous Hepa1-6 HCC model and decreased the frequency of CD8(+)CD122(+) Tregs in the tumor as well as lymph nodes and spleen of the tumor-bearing mice. It also increased the percentage of IFN-γ-expressing CD8(+) T cells in the tumor and peripheral lymphoid organs. The antitumor effects of resveratrol were partially reversed by the adoptive transfer of exogenous CD8(+)CD122(+) Tregs into the tumor-bearing mice. Meanwhile, resveratrol treatment downregulated immunosuppressive cytokines, including TGF-β1 and interleukin-10, in the tumor while elevating antitumor cytokines, TNF-α and IFN-γ. It also inhibited the activation of STAT3 signaling in the tumor. As expected, resveratrol reduced the percentage of M2-like macrophages in the mice. Importantly, resveratrol suppressed orthotopic H22 tumor growth and decreased the frequency of CD8(+)CD122(+) Tregs and M2-like macrophages in the tumor-bearing mice. Furthermore, our studies showed that resveratrol, at non-cytotoxic concentrations, inhibited CD8(+)CD122(+) Treg differentiation from CD8(+)CD122(−) T cells in vitro. Thus, our studies unveiled a new immune mechanism underlying the immunosuppressive tumor microenvironment and demonstrated that resveratrol could help reverse it by diminishing CD8(+)CD122(+) Tregs. Taylor & Francis 2020-10-24 /pmc/articles/PMC7588216/ /pubmed/33150044 http://dx.doi.org/10.1080/2162402X.2020.1829346 Text en © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Zhang, Qunfang
Huang, Haiding
Zheng, Fang
Liu, Huazhen
Qiu, Feifei
Chen, Yuchao
Liang, Chun-Ling
Dai, Zhenhua
Resveratrol exerts antitumor effects by downregulating CD8(+)CD122(+) Tregs in murine hepatocellular carcinoma
title Resveratrol exerts antitumor effects by downregulating CD8(+)CD122(+) Tregs in murine hepatocellular carcinoma
title_full Resveratrol exerts antitumor effects by downregulating CD8(+)CD122(+) Tregs in murine hepatocellular carcinoma
title_fullStr Resveratrol exerts antitumor effects by downregulating CD8(+)CD122(+) Tregs in murine hepatocellular carcinoma
title_full_unstemmed Resveratrol exerts antitumor effects by downregulating CD8(+)CD122(+) Tregs in murine hepatocellular carcinoma
title_short Resveratrol exerts antitumor effects by downregulating CD8(+)CD122(+) Tregs in murine hepatocellular carcinoma
title_sort resveratrol exerts antitumor effects by downregulating cd8(+)cd122(+) tregs in murine hepatocellular carcinoma
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588216/
https://www.ncbi.nlm.nih.gov/pubmed/33150044
http://dx.doi.org/10.1080/2162402X.2020.1829346
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