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

Hanna BS, Llao-Cid L, Iskar M, Roessner PM, Klett LC, Wong JKL, Paul Y, Ioannou N, Ozturk S, Mack N, Kalter V, Colomer D, Campo E, Bloehdorn J, Stilgenbauer S, Dietrich S, Schmidt M, Gabriel R, Rippe K, Feuerer M, Ramsay AG, Lichter P, Zapatka M, Seiffert M (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Immunity Elsevier

Book Volume: 54

Pages Range: 2825-2841.e10

Journal Issue: 12

DOI: 10.1016/j.immuni.2021.11.004

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.

Involved external institutions

Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) King’s College London GB United Kingdom (GB) Universitat de Barcelona (UB) / University of Barcelona ES Spain (ES) Universität Ulm DE Germany (DE) Universitätsklinikum Heidelberg DE Germany (DE)

How to cite

APA:

Hanna, B.S., Llao-Cid, L., Iskar, M., Roessner, P.M., Klett, L.C., Wong, J.K.L.,... Seiffert, M. (2021). Interleukin-10 receptor signaling promotes the maintenance of a PD-1int TCF-1+ CD8+ T cell population that sustains anti-tumor immunity. Immunity, 54(12), 2825-2841.e10. https://doi.org/10.1016/j.immuni.2021.11.004

MLA:

Hanna, Bola S., et al. "Interleukin-10 receptor signaling promotes the maintenance of a PD-1int TCF-1+ CD8+ T cell population that sustains anti-tumor immunity." Immunity 54.12 (2021): 2825-2841.e10.

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