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; Philipp Beckhove

doi:10.1038/s41467-021-21297-y

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 DomschkeManfred Schmidt, Christof von Kalle, Florian Schütz, Thierry Voet, Philipp Beckhove^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

36 Citations (Scopus)

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.

Original language	English
Article number	1119
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21297-y
Publication status	Published - 1 Dec 2021
Externally published	Yes

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Xydia, M., Rahbari, R., Ruggiero, E., Macaulay, I., Tarabichi, M., Lohmayer, R., Wilkening, S., Michels, T., Brown, D., Vanuytven, S., Mastitskaya, S., Laidlaw, S., Grabe, N., Pritsch, M., Fronza, R., Hexel, K., Schmitt, S., Müller-Steinhardt, M., Halama, N., ... Beckhove, P. (2021). Common clonal origin of conventional T cells and induced regulatory T cells in breast cancer patients. Nature Communications, 12(1), Article 1119. https://doi.org/10.1038/s41467-021-21297-y

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title = "Common clonal origin of conventional T cells and induced regulatory T cells in breast cancer patients",

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.",

author = "Maria Xydia and Raheleh Rahbari and Eliana Ruggiero and Iain Macaulay and Maxime Tarabichi and Robert Lohmayer and Stefan Wilkening and Tillmann Michels and Daniel Brown and Sebastiaan Vanuytven and Svetlana Mastitskaya and Sean Laidlaw and Niels Grabe and Maria Pritsch and Raffaele Fronza and Klaus Hexel and Steffen Schmitt and Michael M{\"u}ller-Steinhardt and Niels Halama and Christoph Domschke and Manfred Schmidt and {von Kalle}, Christof and Florian Sch{\"u}tz and Thierry Voet and Philipp Beckhove",

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doi = "10.1038/s41467-021-21297-y",

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Xydia, M, Rahbari, R, Ruggiero, E, Macaulay, I, Tarabichi, M, Lohmayer, R, Wilkening, S, Michels, T, Brown, D, Vanuytven, S, Mastitskaya, S, Laidlaw, S, Grabe, N, Pritsch, M, Fronza, R, Hexel, K, Schmitt, S, Müller-Steinhardt, M, Halama, N, Domschke, C, Schmidt, M, von Kalle, C, Schütz, F, Voet, T & Beckhove, P 2021, 'Common clonal origin of conventional T cells and induced regulatory T cells in breast cancer patients', Nature Communications, vol. 12, no. 1, 1119. https://doi.org/10.1038/s41467-021-21297-y

TY - JOUR

T1 - Common clonal origin of conventional T cells and induced regulatory T cells in breast cancer patients

AU - Xydia, Maria

AU - Rahbari, Raheleh

AU - Ruggiero, Eliana

AU - Macaulay, Iain

AU - Tarabichi, Maxime

AU - Lohmayer, Robert

AU - Wilkening, Stefan

AU - Michels, Tillmann

AU - Brown, Daniel

AU - Vanuytven, Sebastiaan

AU - Mastitskaya, Svetlana

AU - Laidlaw, Sean

AU - Grabe, Niels

AU - Pritsch, Maria

AU - Fronza, Raffaele

AU - Hexel, Klaus

AU - Schmitt, Steffen

AU - Müller-Steinhardt, Michael

AU - Halama, Niels

AU - Domschke, Christoph

AU - Schmidt, Manfred

AU - von Kalle, Christof

AU - Schütz, Florian

AU - Voet, Thierry

AU - Beckhove, Philipp

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85101218252&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-21297-y

DO - 10.1038/s41467-021-21297-y

M3 - Article

C2 - 33602930

AN - SCOPUS:85101218252

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1119

ER -

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

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