Common clonal origin of conventional T cells and induced regulatory T cells in breast cancer patients

Xydia, Maria, Rahbari, Raheleh, Ruggiero, Eliana, Macaulay, Iain, Tarabichi, Maxime, Lohmayer, Robert, Wilkening, Stefan, Michels, Tillmann, Brown, Daniel, Vanuytven, Sebastiaan, Mastitskaya, Svetlana, Laidlaw, Sean, Grabe, Niels, Pritsch, Maria, Fronza, Raffaele, Hexel, Klaus, Schmitt, Steffen, Müller-Steinhardt, Michael, Halama, Niels, Domschke, Christoph, Schmidt, Manfred, von Kalle, Christof, Schütz, Florian, Voet, Thierry and Beckhove, Philipp (2021) Common clonal origin of conventional T cells and induced regulatory T cells in breast cancer patients. Nature Communications, 12. ISSN 2041-1723

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Regulatory CD4+ T cells (Treg) prevent tumor clearance by conventional T cells (Tconv) comprising a major obstacle of cancer immune-surveillance. Hitherto, the mechanisms of Treg repertoire formation in human cancers remain largely unclear. Here, we analyze Treg clonal origin in breast cancer patients using T-Cell Receptor and single-cell transcriptome sequencing. While Treg in peripheral blood and breast tumors are clonally distinct, Tconv clones, including tumor-antigen reactive effectors (Teff), are detected in both compartments. Tumor-infiltrating CD4+ cells accumulate into distinct transcriptome clusters, including early activated Tconv, uncommitted Teff, Th1 Teff, suppressive Treg and pro-tumorigenic Treg. Trajectory analysis suggests early activated Tconv differentiation either into Th1 Teff or into suppressive and pro-tumorigenic Treg. Importantly, Tconv, activated Tconv and Treg share highly-expanded clones contributing up to 65% of intratumoral Treg. Here we show that Treg in human breast cancer may considerably stem from antigen-experienced Tconv converting into secondary induced Treg through intratumoral activation.

Item Type: Article
Additional Information: Funding Information: This work was funded by the Collaborative Research Program (SFB TR221). R.R. is a recipient of a CRUK Career Development fellowship (C66259/A27114). The work of M.T. was supported by The Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202), and the Wellcome Trust (FC001202) (M.T.). M.T. is supported as a postdoctoral fellow by the European Union’s Horizon 2020 research and innovation program (Marie Skłodowska-Curie grant agreement no. 747852-SIOMICS). This project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the UK Medical Research Council (grant no. MR/L016311/1) (M.T.). T.V. is supported by KU Leuven (SymBioSys – C14/18/092), the Foundation against Cancer (2015-143), and the Research Foundation Flanders (FWO I001818N); S.V. is supported by a PhD fellowship for Strategic Basic Research (1S93320N) from the Research Foundation Flanders (FWO) and D.B. by a FWO [PEGASUS]2 Marie Skłodowska-Curie Fellowship (12O5617N).
Uncontrolled Keywords: chemistry(all),biochemistry, genetics and molecular biology(all),physics and astronomy(all),sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1600
Faculty \ School: Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 02 Nov 2022 09:30
Last Modified: 07 Nov 2022 00:49
DOI: 10.1038/s41467-021-21297-y


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