Immunophenotype of gastric tumors unveils a pleiotropic role of regulatory T cells in tumor development
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2021 |
| Outros Autores: | , , , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| Texto Completo: | http://hdl.handle.net/10451/46207 |
Resumo: | Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
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Immunophenotype of gastric tumors unveils a pleiotropic role of regulatory T cells in tumor developmentTumor-infiltrating CD4 T cellsRegulatory T cellsMolecular regulationGastric cancerCopyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Gastric cancer (GC) patients display increased regulatory T cell (Tregs) numbers in peripheral blood and among tumor-infiltrating lymphocytes. Nevertheless, the role of Tregs in GC progression remains controversial. Here, we sought to explore the impact of Tregs in GCs with distinct histology, and whether Tregs can directly influence tumor cell behavior and GC development. We performed a comprehensive immunophenotyping of 82 human GC cases, through an integrated analysis of multispectral immunofluorescence detection of T cells markers and patient clinicopathological data. Moreover, we developed 3D in vitro co-cultures with Tregs and tumor cells that were followed by high-throughput and light-sheet imaging, and their biological features studied with conventional/imaging flow cytometry and Western blotting. We showed that Tregs located at the tumor nest were frequent in intestinal-type GCs but did not associate with increased levels of effector T cells. Our in vitro results suggested that Tregs preferentially infiltrated intestinal-type GC spheroids, induced the expression of IL2Rα and activation of MAPK signaling pathway in tumor cells, and promoted spheroid growth. Accumulation of Tregs in intestinal-type GCs was increased at early stages of the stomach wall invasion and in the absence of vascular and perineural invasion. In this study, we proposed a non-immunosuppressive mechanism through which Tregs might directly modulate GC cells and thereby promote tumor growth. Our findings hold insightful implications for therapeutic strategies targeting intestinal-type GCs and other tumors with similar immune context.This work was supported by grants: (1) “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274), by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020— Operacional Program for Competitiveness and Internationalisation (POCI), PORTUGAL 2020, Portuguese funds through Portuguese Science & Technology Foundation (FCT)/Ministério da Ciência, Tecnologia e Inovação; (2) Project CANCER Ref. NORTE-01-0145-FEDER-000029 and DOCnet Ref. NORTE-01-0145-FEDER-000003), by Norte Portugal Regional Program (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF); (3) Project Ref. PTDC/BBB-ECT/2518/2014, by FCT;(4) FCT PhD Programs and by Programa Operacional Potencial Humano (POCH), specifically by the Biotech Health Programe (Doctoral Program on Cellular and Molecular Biotechnology Applied to Health Sciences); (5) “The role of gastric cancer cell-derived extracellular vesicles”, by IPATIMUP Board of Directors; (6) GenomePT project (POCI-01-0145-FEDER-022184), by COMPETE 2020—POCI, Lisboa Portugal Regional Operational Program (Lisboa2020), Algarve Portugal Regional Operational Program (CRESC Algarve2020), under the PORTUGAL 2020 Partnership Agreement, through ERDF, and by FCT; (7) Marie Skłodowska-Curie grant agreement No. 722148 to Train-EV project by Euro-pean Union’s Horizon 2020 research and innovation program; 8) Project CANCERSTEM funded by ERDF, POCI and FCT; 9) FCT fellowship PD/BD/128406/2017 to SR, and Junior Research contractto JC (regulated by the decree-law 57/2016 emended by law 57/2017). IPATIMUP integrates the i3S Research Unit, which is partially supported by FCT. NFCCdM has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 852832). The authors acknowledgethe support of the Advanced Light Microscopy, Bioimaging, BioSciences Screening and Histologyand Electron Microscopy i3S Scientific Platforms members of the national infrastructure PPBI—Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122), and the support providedby the Translational Cytometry i3S Scientific Platforms.MDPIRepositório da Universidade de LisboaRocha, SaraBasto, AfonsoIjsselsteijn, Marieke E.Teles, Sara P.Azevedo, Maria M.Gonçalves, GilzaGullo, IreneAlmeida, Gabriela M.Maqueda, Joaquín J.Oliveira, Marta I.Carneiro, FátimaBarata, João T.Graca, Luisde Miranda, Noel F. C. C.Carvalho, JoanaOliveira, Carla2021-02-05T14:27:23Z20212021-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/46207engCancers 2021, 13, 421.10.3390/cancers130304212072-6694info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-11-20T18:03:10Zoai:repositorio.ul.pt:10451/46207Portal AgregadorONGhttps://www.rcaap.pt/oai/openairemluisa.alvim@gmail.comopendoar:71602024-11-20T18:03:10Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
| dc.title.none.fl_str_mv |
Immunophenotype of gastric tumors unveils a pleiotropic role of regulatory T cells in tumor development |
| title |
Immunophenotype of gastric tumors unveils a pleiotropic role of regulatory T cells in tumor development |
| spellingShingle |
Immunophenotype of gastric tumors unveils a pleiotropic role of regulatory T cells in tumor development Rocha, Sara Tumor-infiltrating CD4 T cells Regulatory T cells Molecular regulation Gastric cancer |
| title_short |
Immunophenotype of gastric tumors unveils a pleiotropic role of regulatory T cells in tumor development |
| title_full |
Immunophenotype of gastric tumors unveils a pleiotropic role of regulatory T cells in tumor development |
| title_fullStr |
Immunophenotype of gastric tumors unveils a pleiotropic role of regulatory T cells in tumor development |
| title_full_unstemmed |
Immunophenotype of gastric tumors unveils a pleiotropic role of regulatory T cells in tumor development |
| title_sort |
Immunophenotype of gastric tumors unveils a pleiotropic role of regulatory T cells in tumor development |
| author |
Rocha, Sara |
| author_facet |
Rocha, Sara Basto, Afonso Ijsselsteijn, Marieke E. Teles, Sara P. Azevedo, Maria M. Gonçalves, Gilza Gullo, Irene Almeida, Gabriela M. Maqueda, Joaquín J. Oliveira, Marta I. Carneiro, Fátima Barata, João T. Graca, Luis de Miranda, Noel F. C. C. Carvalho, Joana Oliveira, Carla |
| author_role |
author |
| author2 |
Basto, Afonso Ijsselsteijn, Marieke E. Teles, Sara P. Azevedo, Maria M. Gonçalves, Gilza Gullo, Irene Almeida, Gabriela M. Maqueda, Joaquín J. Oliveira, Marta I. Carneiro, Fátima Barata, João T. Graca, Luis de Miranda, Noel F. C. C. Carvalho, Joana Oliveira, Carla |
| author2_role |
author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
| dc.contributor.author.fl_str_mv |
Rocha, Sara Basto, Afonso Ijsselsteijn, Marieke E. Teles, Sara P. Azevedo, Maria M. Gonçalves, Gilza Gullo, Irene Almeida, Gabriela M. Maqueda, Joaquín J. Oliveira, Marta I. Carneiro, Fátima Barata, João T. Graca, Luis de Miranda, Noel F. C. C. Carvalho, Joana Oliveira, Carla |
| dc.subject.por.fl_str_mv |
Tumor-infiltrating CD4 T cells Regulatory T cells Molecular regulation Gastric cancer |
| topic |
Tumor-infiltrating CD4 T cells Regulatory T cells Molecular regulation Gastric cancer |
| description |
Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021-02-05T14:27:23Z 2021 2021-01-01T00:00:00Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
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http://hdl.handle.net/10451/46207 |
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http://hdl.handle.net/10451/46207 |
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eng |
| language |
eng |
| dc.relation.none.fl_str_mv |
Cancers 2021, 13, 421. 10.3390/cancers13030421 2072-6694 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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MDPI |
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MDPI |
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