{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Van Meerbeeck P"],"funding":["FNRS","Fonds De La Recherche Scientifique - FNRS","WEL Research Institute, WELBIO Department"],"pagination":["308"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12433403"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["74(10)"],"pubmed_abstract":["Most cells produce latent transforming growth factor-beta 1 (TGF-β1), but only very few activate the cytokine via cell type-specific mechanisms. TGF-β1 favors cancer progression by suppressing anti-tumor T cell responses. Which cells produce this immunosuppressive TGF-β1 in human tumors is unknown. Putative sources include cells expressing the glycoprotein A repetitions predominant (GARP) protein, comprising mostly activated regulatory T cells (Tregs) (GARP<sup>+</sup>FOXP3<sup>+</sup> cells) and blood endothelial cells (BECs). We performed multiplexed immunohistofluorescence and computerized image analyses on 186 tumor samples from 5 cancer types (colorectal, urothelial, lung and breast primary carcinomas and melanoma metastases), compared to patient-matched adjacent non-cancerous tissues. GARP<sup>+</sup> Tregs were present in 29-75% of the various types of tumor samples. Their proportion was higher in tumors than non-cancerous tissues but unexpectedly it did not correlate with that of tumor-infiltrating T lymphocytes (TILs). The density of blood vessels was similar across samples, with more than half expressing GARP. The proportion of cells undergoing TGF-β1 signaling, which express the phosphorylated form of mothers against decapentaplegic homolog 2 (pSMAD2), was approximately twice as high in tumors compared to non-cancerous tissues. In most tumor types, pSMAD2<sup>+</sup> TILs were twice closer to the nearest FOXP3<sup>+</sup> cell than after random repositioning, at a distance (~ 70 µm) consistent with short-range paracrine TGF-β1 signaling. In contrast, pSMAD2<sup>+</sup> non-T cells and pSMAD2<sup>-</sup> TILs were not closer to FOXP3<sup>+</sup> cells, neither were pSMAD2<sup>+</sup> cells (TILs and others) to BECs. We conclude that, in human tumors, GARP-expressing Tregs rather than BECs appear to represent a source of TGF-β1 suppressing nearby TILs. This local immunosuppression could be blocked with anti-GARP:TGF-β1 antibodies, particularly to treat patients with tumors heavily infiltrated by GARP-expressing Tregs."],"journal":["Cancer immunology, immunotherapy : CII"],"pubmed_title":["GARP-expressing Tregs as a source of immunosuppressive TGF-β1 in human tumors."],"pmcid":["PMC12433403"],"funding_grant_id":["PDR-TLV#40007447","CR-2019A-02 and CR-2019A-02 R","PDR-TLV#40007289","Postdoctoral Researcher"],"pubmed_authors":["Marbaix E","Maatougui D","de Streel G","Aboubakar Nana F","Van den Eynde M","Carrasco J","Van Meerbeeck P","Noel A","Vaherto N","Lucas S","Devaux A","van Baren N"],"additional_accession":[]},"is_claimable":false,"name":"GARP-expressing Tregs as a source of immunosuppressive TGF-β1 in human tumors.","description":"Most cells produce latent transforming growth factor-beta 1 (TGF-β1), but only very few activate the cytokine via cell type-specific mechanisms. TGF-β1 favors cancer progression by suppressing anti-tumor T cell responses. Which cells produce this immunosuppressive TGF-β1 in human tumors is unknown. Putative sources include cells expressing the glycoprotein A repetitions predominant (GARP) protein, comprising mostly activated regulatory T cells (Tregs) (GARP<sup>+</sup>FOXP3<sup>+</sup> cells) and blood endothelial cells (BECs). We performed multiplexed immunohistofluorescence and computerized image analyses on 186 tumor samples from 5 cancer types (colorectal, urothelial, lung and breast primary carcinomas and melanoma metastases), compared to patient-matched adjacent non-cancerous tissues. GARP<sup>+</sup> Tregs were present in 29-75% of the various types of tumor samples. Their proportion was higher in tumors than non-cancerous tissues but unexpectedly it did not correlate with that of tumor-infiltrating T lymphocytes (TILs). The density of blood vessels was similar across samples, with more than half expressing GARP. The proportion of cells undergoing TGF-β1 signaling, which express the phosphorylated form of mothers against decapentaplegic homolog 2 (pSMAD2), was approximately twice as high in tumors compared to non-cancerous tissues. In most tumor types, pSMAD2<sup>+</sup> TILs were twice closer to the nearest FOXP3<sup>+</sup> cell than after random repositioning, at a distance (~ 70 µm) consistent with short-range paracrine TGF-β1 signaling. In contrast, pSMAD2<sup>+</sup> non-T cells and pSMAD2<sup>-</sup> TILs were not closer to FOXP3<sup>+</sup> cells, neither were pSMAD2<sup>+</sup> cells (TILs and others) to BECs. We conclude that, in human tumors, GARP-expressing Tregs rather than BECs appear to represent a source of TGF-β1 suppressing nearby TILs. This local immunosuppression could be blocked with anti-GARP:TGF-β1 antibodies, particularly to treat patients with tumors heavily infiltrated by GARP-expressing Tregs.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Sep","modification":"2026-06-01T14:06:33.71Z","creation":"2026-04-08T13:19:11.638Z"},"accession":"S-EPMC12433403","cross_references":{"pubmed":["40944768"],"doi":["10.1007/s00262-025-04157-2"]}}