Direct and Indirect Effect of TGFβ on Treg Transendothelial Recruitment in HCC Tissue Microenvironment

The balance between anti-tumor and tumor-promoting immune cells, such as CD4+ Th1 and regulatory T cells (Tregs), respectively, is assumed to dictate the progression of hepatocellular carcinoma (HCC). The transforming growth factor beta (TGFβ) markedly shapes the HCC microenvironment, regulating the...

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Autores principales:	Francesco Dituri, Serena Mancarella, Grazia Serino, Nada Chaoul, Luigi Giovanni Lupo, Erica Villa, Isabel Fabregat, Gianluigi Giannelli
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	HCC TGF beta cancer immunity regulatory T cells cancer-associated fibroblasts transendothelial migration Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/c90e38a8b00d4aaca1ef67cb9ba119a3
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spelling	oai:doaj.org-article:c90e38a8b00d4aaca1ef67cb9ba119a32021-11-11T17:13:00ZDirect and Indirect Effect of TGFβ on Treg Transendothelial Recruitment in HCC Tissue Microenvironment10.3390/ijms2221117651422-00671661-6596https://doaj.org/article/c90e38a8b00d4aaca1ef67cb9ba119a32021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11765https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067The balance between anti-tumor and tumor-promoting immune cells, such as CD4+ Th1 and regulatory T cells (Tregs), respectively, is assumed to dictate the progression of hepatocellular carcinoma (HCC). The transforming growth factor beta (TGFβ) markedly shapes the HCC microenvironment, regulating the activation state of multiple leukocyte subsets and driving the differentiation of cancer associated fibroblasts (CAFs). The fibrotic (desmoplastic) reaction in HCC tissue strongly depends on CAFs activity. In this study, we attempted to assess the role of TGFβ on transendothelial migration of Th1-oriented and Treg-oriented CD4+ T cells via a direct or indirect, CAF-mediated mechanisms, respectively. We found that the blockage of TGFβ receptor I-dependent signaling in Tregs resulted in impaired transendothelial migration (TEM) of these cells. Interestingly, the secretome of TGFβ-treated CAFs inhibited the TEM of Tregs but not Th1 cells, in comparison to the secretome of untreated CAFs. In addition, we found a significant inverse correlation between alpha-SMA and FoxP3 (marker of Tregs) mRNA expression in a microarray analysis involving 78 HCCs, thus suggesting that TGFβ-activated stromal cells may counteract the trafficking of Tregs into the tumor. The apparent dual behavior of TGFβ as both pro- and anti-tumorigenic cytokines may add a further level of complexity to the mechanisms that regulate the interactions among cancerous, stromal, and immune cells within HCC, as well as other solid tumors, and contribute to better manipulation of the TGFβ signaling as a therapeutic target in HCC patients.Francesco DituriSerena MancarellaGrazia SerinoNada ChaoulLuigi Giovanni LupoErica VillaIsabel FabregatGianluigi GiannelliMDPI AGarticleHCCTGF betacancer immunityregulatory T cellscancer-associated fibroblaststransendothelial migrationBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11765, p 11765 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	HCC TGF beta cancer immunity regulatory T cells cancer-associated fibroblasts transendothelial migration Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	HCC TGF beta cancer immunity regulatory T cells cancer-associated fibroblasts transendothelial migration Biology (General) QH301-705.5 Chemistry QD1-999 Francesco Dituri Serena Mancarella Grazia Serino Nada Chaoul Luigi Giovanni Lupo Erica Villa Isabel Fabregat Gianluigi Giannelli Direct and Indirect Effect of TGFβ on Treg Transendothelial Recruitment in HCC Tissue Microenvironment
description	The balance between anti-tumor and tumor-promoting immune cells, such as CD4+ Th1 and regulatory T cells (Tregs), respectively, is assumed to dictate the progression of hepatocellular carcinoma (HCC). The transforming growth factor beta (TGFβ) markedly shapes the HCC microenvironment, regulating the activation state of multiple leukocyte subsets and driving the differentiation of cancer associated fibroblasts (CAFs). The fibrotic (desmoplastic) reaction in HCC tissue strongly depends on CAFs activity. In this study, we attempted to assess the role of TGFβ on transendothelial migration of Th1-oriented and Treg-oriented CD4+ T cells via a direct or indirect, CAF-mediated mechanisms, respectively. We found that the blockage of TGFβ receptor I-dependent signaling in Tregs resulted in impaired transendothelial migration (TEM) of these cells. Interestingly, the secretome of TGFβ-treated CAFs inhibited the TEM of Tregs but not Th1 cells, in comparison to the secretome of untreated CAFs. In addition, we found a significant inverse correlation between alpha-SMA and FoxP3 (marker of Tregs) mRNA expression in a microarray analysis involving 78 HCCs, thus suggesting that TGFβ-activated stromal cells may counteract the trafficking of Tregs into the tumor. The apparent dual behavior of TGFβ as both pro- and anti-tumorigenic cytokines may add a further level of complexity to the mechanisms that regulate the interactions among cancerous, stromal, and immune cells within HCC, as well as other solid tumors, and contribute to better manipulation of the TGFβ signaling as a therapeutic target in HCC patients.
format	article
author	Francesco Dituri Serena Mancarella Grazia Serino Nada Chaoul Luigi Giovanni Lupo Erica Villa Isabel Fabregat Gianluigi Giannelli
author_facet	Francesco Dituri Serena Mancarella Grazia Serino Nada Chaoul Luigi Giovanni Lupo Erica Villa Isabel Fabregat Gianluigi Giannelli
author_sort	Francesco Dituri
title	Direct and Indirect Effect of TGFβ on Treg Transendothelial Recruitment in HCC Tissue Microenvironment
title_short	Direct and Indirect Effect of TGFβ on Treg Transendothelial Recruitment in HCC Tissue Microenvironment
title_full	Direct and Indirect Effect of TGFβ on Treg Transendothelial Recruitment in HCC Tissue Microenvironment
title_fullStr	Direct and Indirect Effect of TGFβ on Treg Transendothelial Recruitment in HCC Tissue Microenvironment
title_full_unstemmed	Direct and Indirect Effect of TGFβ on Treg Transendothelial Recruitment in HCC Tissue Microenvironment
title_sort	direct and indirect effect of tgfβ on treg transendothelial recruitment in hcc tissue microenvironment
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/c90e38a8b00d4aaca1ef67cb9ba119a3
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_version_	1718432144412377088

Direct and Indirect Effect of TGFβ on Treg Transendothelial Recruitment in HCC Tissue Microenvironment

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