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Interleukin-10 receptor signaling promotes the maintenance of a PD-1int TCF-1+ CD8+ T cell population that sustains anti-tumor immunity

Research output: Contribution to journalArticlepeer-review

Bola S. Hanna, Laura Llaó-Cid, Murat Iskar, Philipp M. Roessner, Lara C. Klett, John K.L. Wong, Yashna Paul, Nikolaos Ioannou, Selcen Öztürk, Norman Mack, Verena Kalter, Dolors Colomer, Elías Campo, Johannes Bloehdorn, Stephan Stilgenbauer, Sascha Dietrich, Manfred Schmidt, Richard Gabriel, Karsten Rippe, Markus Feuerer & 4 more Alan G. Ramsay, Peter Lichter, Marc Zapatka, Martina Seiffert

Original languageEnglish
Pages (from-to)2825-2841.e10
JournalImmunity
Volume54
Issue number12
Early online date7 Dec 2021
DOIs
E-pub ahead of print7 Dec 2021
Published14 Dec 2021

Bibliographical note

Funding Information: We thank Dietmar Zehn (Technical University of Munich, Germany) for scientific discussions and input and Christoph Schiffler (DKFZ) for experimental support. Thanks also to the Central Animal Laboratory, the Single-cell Open Lab, and the Genomics and Proteomics Core Facility at the DKFZ, to the Nikon Imaging Facility at King's College London for technical assistance, and to Michael Hain for computational support. We further thank Ulrike Tr?ger (DKFZ) for editing the material and methods part of this manuscript and Clemens Neufert (University Clinic Erlangen, Germany) and Ekaterina Lupar (Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany) for providing Stat3-deficient and FIR ? tiger mice, respectively. This study was supported by the German Research Foundation (DFG) project EV-RNA (SE 2331/2-1), by the Eurostars project E!10865 - LeukeMab (01QE1716), funded by the German Ministry of Education and Research (BMBF), by the German Jos? Carreras Foundation (grant 13R/2018) to M. Seiffert, by the German Cancer Aid to M. Seiffert (grant no. 70114114) and to P.M.R. (grant no. 112069), by an NCT 3.0 funding program (NCT3.0_2015.13 ImmunOmics, NCT3.0_2015.2 SPL/RP) to M. Schmidt and R.G. by a grant from Ministerio de Ciencia e Innovaci?n and ERDF (SAF15-67633-R) to D.C. by the ?la Caixa? Foundation (CLLEvolution-LCF/PR/HR17/52150017, Health Research 2017 Program HR17-00221) and the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No 810287, BCLLatlas) to E.C. by the DFG (SFB1074 project B1) to St.St. by a grant from the ERC (ERC-CoG, #648145 REGiREG) to M.F. and by the BMBF-Network ?PRECiSe? (031L0076A) and the ERA-NET TRANSCAN-2 program JTC 2014?project FIRE-CLL to St.St. P.L. and M. Seiffert. The graphical abstract was created using BioRender.com. B.S.H. designed the study, performed experiments, analyzed data, generated figures, and wrote the paper. L.L-C. was involved in the conceptual design of the study, performed experiments, analyzed data, generated figures, and wrote the paper. M.I. performed bioinformatical analyses, generated figures, and wrote parts of the paper. P.M.R. performed experiments, analyzed data, and generated figures. J.K.L.W. and Y.P. analyzed scRNA-seq data and generated figures. L.C.K. and K.R. performed ATAC-seq, analyzed data, and generated figures. K.R. helped with editing the text. N.I. and A.G.R. performed cell conjugation and immunological synapse assays, analyzed data, and generated figures. S.?. N.M. and V.K. conducted experiments. D.C. E.C. J.B. St.St. and S.D. provided clinical samples and information and performed correlation analyses. M. Schmidt and R.G. performed TCR sequencing, analyzed data, and generated figures. M.F. was involved in discussions regarding experimental protocols and data, as well as in paper writing. P.L. provided logistic and budget support and was involved in discussions and paper writing. M.Z. performed and supervised bioinformatical analyses and interpreted and discussed data. M. Seiffert designed the study, interpreted and discussed data, provided logistic and budget support, and wrote the paper. The authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. Funding Information: This study was supported by the German Research Foundation (DFG) project EV-RNA ( SE 2331/2-1 ), by the Eurostars project E!10865 - LeukeMab ( 01QE1716 ), funded by the German Ministry of Education and Research (BMBF), by the German José Carreras Foundation (grant 13R/2018 ) to M. Seiffert, by the German Cancer Aid to M. Seiffert (grant no. 70114114 ) and to P.M.R. (grant no. 112069 ), by an NCT 3.0 funding program ( NCT3.0_2015.13 ImmunOmics , NCT3.0_2015.2 SPL/RP ) to M. Schmidt and R.G., by a grant from Ministerio de Ciencia e Innovación and ERDF ( SAF15-67633-R ) to D.C., by the “la Caixa” Foundation ( CLLEvolution-LCF/PR/HR17/52150017 , Health Research 2017 Program HR17-00221 ) and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 810287 , BCLLatlas) to E.C., by the DFG ( SFB1074 project B1 ) to St.St., by a grant from the ERC (ERC-CoG, # 648145 REGiREG) to M.F., and by the BMBF-Network “PRECiSe” ( 031L0076A ) and the ERA-NET TRANSCAN-2 program JTC 2014–project FIRE-CLL to St.St., P.L., and M. Seiffert. Publisher Copyright: © 2021 Elsevier Inc.

King's Authors

Abstract

T cell exhaustion limits anti-tumor immunity and responses to immunotherapy. Here, we explored the microenvironmental signals regulating T cell exhaustion using a model of chronic lymphocytic leukemia (CLL). Single-cell analyses identified a subset of PD-1hi, functionally impaired CD8+ T cells that accumulated in secondary lymphoid organs during disease progression and a functionally competent PD-1int subset. Frequencies of PD-1int TCF-1+ CD8+ T cells decreased upon Il10rb or Stat3 deletion, leading to accumulation of PD-1hi cells and accelerated tumor progression. Mechanistically, inhibition of IL-10R signaling altered chromatin accessibility and disrupted cooperativity between the transcription factors NFAT and AP-1, promoting a distinct NFAT-associated program. Low IL10 expression or loss of IL-10R-STAT3 signaling correlated with increased frequencies of exhausted CD8+ T cells and poor survival in CLL and in breast cancer patients. Thus, balance between PD-1hi, exhausted CD8+ T cells and functional PD-1int TCF-1+ CD8+ T cells is regulated by cell-intrinsic IL-10R signaling, with implications for immunotherapy.

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