%0 Journal Article
%A Hanna, Bola S
%A Llaó-Cid, Laura
%A Iskar, Murat
%A Roessner, Philipp M
%A Klett, Lara C
%A Wong, John K L
%A Paul, Yashna
%A Ioannou, Nikolaos
%A Öztürk, Selcen
%A Mack, Norman
%A Kalter, Verena
%A Colomer, Dolors
%A Campo, Elías
%A Bloehdorn, Johannes
%A Stilgenbauer, Stephan
%A Dietrich, Sascha
%A Schmidt, Manfred
%A Gabriel, Richard
%A Rippe, Karsten
%A Feuerer, Markus
%A Ramsay, Alan G
%A Lichter, Peter
%A Zapatka, Marc
%A Seiffert, Martina
%T Interleukin-10 receptor signaling promotes the maintenance of a PD-1int TCF-1+ CD8+ T cell population that sustains anti-tumor immunity.
%J Immunity
%V 54
%N 12
%@ 1074-7613
%C New York, NY
%I Elsevier
%M DKFZ-2021-03072
%P 2825-2841.e10
%D 2021
%Z #EA:B060#LA:B060# / 2021 Dec 14;54(12):2825-2841.e10
%X 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.
%K CD8(+) T cells (Other)
%K CLL (Other)
%K IL-10 (Other)
%K IL-10R (Other)
%K NFAT (Other)
%K PD-1 heterogeneity (Other)
%K STAT3 (Other)
%K T cell exhaustion (Other)
%K TCF-1 (Other)
%K tumor microenvironment (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:34879221
%R 10.1016/j.immuni.2021.11.004
%U https://inrepo02.dkfz.de/record/178063