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

Maria Xydia (), Raheleh Rahbari, Eliana Ruggiero, Iain Macaulay, Maxime Tarabichi, Robert Lohmayer, Stefan Wilkening, Tillmann Michels, Daniel Brown, Sebastiaan Vanuytven, Svetlana Mastitskaya, Sean Laidlaw, Niels Grabe, Maria Pritsch, Raffaele Fronza, Klaus Hexel, Steffen Schmitt, Michael Müller-Steinhardt, Niels Halama, Christoph Domschke, Manfred Schmidt, Christof von Kalle, Florian Schütz, Thierry Voet and Philipp Beckhove ()
Additional contact information
Maria Xydia: University and Department of Hematology/Oncology, University Medical Centre of Regensburg
Raheleh Rahbari: Wellcome Sanger Institute
Eliana Ruggiero: National Centre for Tumor Diseases and German Cancer Research Centre
Iain Macaulay: Wellcome Sanger Institute
Maxime Tarabichi: Wellcome Sanger Institute
Robert Lohmayer: University and Department of Hematology/Oncology, University Medical Centre of Regensburg
Stefan Wilkening: National Centre for Tumor Diseases and German Cancer Research Centre
Tillmann Michels: University and Department of Hematology/Oncology, University Medical Centre of Regensburg
Daniel Brown: University of Leuven, KU Leuven
Sebastiaan Vanuytven: The Francis Crick Institute
Svetlana Mastitskaya: National Centre for Tumor Diseases
Sean Laidlaw: Wellcome Sanger Institute
Niels Grabe: National Centre for Tumor Diseases
Maria Pritsch: German Cancer Research Centre
Raffaele Fronza: National Centre for Tumor Diseases and German Cancer Research Centre
Klaus Hexel: German Cancer Research Centre
Steffen Schmitt: German Cancer Research Centre
Michael Müller-Steinhardt: Medical Faculty Mannheim, Heidelberg University
Niels Halama: National Centre for Tumor Diseases
Christoph Domschke: University Hospital of Heidelberg
Manfred Schmidt: National Centre for Tumor Diseases and German Cancer Research Centre
Christof von Kalle: National Centre for Tumor Diseases and German Cancer Research Centre
Florian Schütz: University Hospital of Heidelberg
Thierry Voet: Wellcome Sanger Institute
Philipp Beckhove: University and Department of Hematology/Oncology, University Medical Centre of Regensburg

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-21297-y

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