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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| Format: | Article |
| Language: | English |
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MDPI AG
2021-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/21/11765 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T06:02:01Z |
| format | Article |
| id | doaj.art-c90e38a8b00d4aaca1ef67cb9ba119a3 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T06:02:01Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c90e38a8b00d4aaca1ef67cb9ba119a32023-11-22T20:57:27ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122211176510.3390/ijms222111765Direct and Indirect Effect of TGFβ on Treg Transendothelial Recruitment in HCC Tissue MicroenvironmentFrancesco Dituri0Serena Mancarella1Grazia Serino2Nada Chaoul3Luigi Giovanni Lupo4Erica Villa5Isabel Fabregat6Gianluigi Giannelli7National Institute for Gastroenterology, IRCCS “S. De Bellis” Research Hospital, 70013 Castellana Grotte, ItalyNational Institute for Gastroenterology, IRCCS “S. De Bellis” Research Hospital, 70013 Castellana Grotte, ItalyNational Institute for Gastroenterology, IRCCS “S. De Bellis” Research Hospital, 70013 Castellana Grotte, ItalyDepartment of Emergency and Organ Transplant, School and Chair of Allergology and Clinical Immunology, University of Bari Medical School, 70124 Bari, ItalyDepartment of General Surgery and Liver Transplantation, University of Bari Medical School, Policlinico, Piazza Giulio Cesare 14, 70124 Bari, ItalyGastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, 41121 Modena, ItalyOncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), CIBEREHD and University of Barcelona, 08908 L’Hospitalet de Llobregat, SpainNational Institute for Gastroenterology, IRCCS “S. De Bellis” Research Hospital, 70013 Castellana Grotte, ItalyThe 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.https://www.mdpi.com/1422-0067/22/21/11765HCCTGF betacancer immunityregulatory T cellscancer-associated fibroblaststransendothelial migration |
| spellingShingle | 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 International Journal of Molecular Sciences HCC TGF beta cancer immunity regulatory T cells cancer-associated fibroblasts transendothelial migration |
| title | 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_short | 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 |
| topic | HCC TGF beta cancer immunity regulatory T cells cancer-associated fibroblasts transendothelial migration |
| url | https://www.mdpi.com/1422-0067/22/21/11765 |
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