TY  - JOUR
AU  - Hanna, Bola S
AU  - Llaó-Cid, Laura
AU  - Iskar, Murat
AU  - Roessner, Philipp M
AU  - Klett, Lara C
AU  - Wong, John K L
AU  - Paul, Yashna
AU  - Ioannou, Nikolaos
AU  - Öztürk, Selcen
AU  - Mack, Norman
AU  - Kalter, Verena
AU  - Colomer, Dolors
AU  - Campo, Elías
AU  - Bloehdorn, Johannes
AU  - Stilgenbauer, Stephan
AU  - Dietrich, Sascha
AU  - Schmidt, Manfred
AU  - Gabriel, Richard
AU  - Rippe, Karsten
AU  - Feuerer, Markus
AU  - Ramsay, Alan G
AU  - Lichter, Peter
AU  - Zapatka, Marc
AU  - Seiffert, Martina
TI  - Interleukin-10 receptor signaling promotes the maintenance of a PD-1int TCF-1+ CD8+ T cell population that sustains anti-tumor immunity.
JO  - Immunity
VL  - 54
IS  - 12
SN  - 1074-7613
CY  - New York, NY
PB  - Elsevier
M1  - DKFZ-2021-03072
SP  - 2825-2841.e10
PY  - 2021
N1  - #EA:B060#LA:B060# / 2021 Dec 14;54(12):2825-2841.e10
AB  - 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.
KW  - CD8(+) T cells (Other)
KW  - CLL (Other)
KW  - IL-10 (Other)
KW  - IL-10R (Other)
KW  - NFAT (Other)
KW  - PD-1 heterogeneity (Other)
KW  - STAT3 (Other)
KW  - T cell exhaustion (Other)
KW  - TCF-1 (Other)
KW  - tumor microenvironment (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:34879221
DO  - DOI:10.1016/j.immuni.2021.11.004
UR  - https://inrepo02.dkfz.de/record/178063
ER  -