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

Autor:	Hanna BS; Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: bola.hanna@hms.harvard.edu., Llaó-Cid L; Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany., Iskar M; Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Roessner PM; Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Klett LC; Chromatin Networks, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Wong JKL; Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Paul Y; Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Ioannou N; School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK., Öztürk S; Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Mack N; Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Kalter V; Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Colomer D; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hematopathology Unit, Pathology Department, Hospital Clinic, CIBERONC, University of Barcelona, 08036 Barcelona, Spain., Campo E; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hematopathology Unit, Pathology Department, Hospital Clinic, CIBERONC, University of Barcelona, 08036 Barcelona, Spain., Bloehdorn J; Internal Medicine III, University of Ulm, 89081 Ulm, Germany., Stilgenbauer S; Internal Medicine III, University of Ulm, 89081 Ulm, Germany., Dietrich S; Medicine V, University Hospital Heidelberg, 69120 Heidelberg, Germany., Schmidt M; Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, 69120 Heidelberg, Germany., Gabriel R; Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, 69120 Heidelberg, Germany., Rippe K; Chromatin Networks, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Feuerer M; Immune Tolerance, Tumor Immunology Program, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Chair for Immunology, Regensburg Center for Interventional Immunology (RCI), University of Regensburg, 93053 Regensburg, Germany., Ramsay AG; School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK., Lichter P; Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Zapatka M; Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Seiffert M; Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: m.seiffert@dkfz.de.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2021 Dec 14; Vol. 54 (12), pp. 2825-2841.e10. Date of Electronic Publication: 2021 Dec 07.
DOI:	10.1016/j.immuni.2021.11.004
Abstrakt:	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-1 hi , functionally impaired CD8 + T cells that accumulated in secondary lymphoid organs during disease progression and a functionally competent PD-1 int subset. Frequencies of PD-1 int TCF-1 + CD8 + T cells decreased upon Il10rb or Stat3 deletion, leading to accumulation of PD-1 hi 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-1 hi , exhausted CD8 + T cells and functional PD-1 int TCF-1 + CD8 + T cells is regulated by cell-intrinsic IL-10R signaling, with implications for immunotherapy. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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