1. Interleukin-10 receptor signaling promotes the maintenance of a PD-1int TCF-1+ CD8+ T cell population that sustains anti-tumor immunity.
- Author
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Hanna, Bola S., Llaó-Cid, Laura, Iskar, Murat, Roessner, Philipp M., Klett, Lara C., Wong, John K.L., Paul, Yashna, Ioannou, Nikolaos, Öztürk, Selcen, Mack, Norman, Kalter, Verena, Colomer, Dolors, Campo, Elías, Bloehdorn, Johannes, Stilgenbauer, Stephan, Dietrich, Sascha, Schmidt, Manfred, Gabriel, Richard, Rippe, Karsten, and Feuerer, Markus
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T cells , *CELL populations , *CD8 antigen , *AP-1 transcription factor , *INTERLEUKIN-10 , *CHRONIC leukemia - 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. [Display omitted] • Heterogeneous PD-1 expression identifies CD8+ T cells with distinct functions in CLL • IL-10 prevents activation-induced exhaustion of CD8+ T cells and reduces CLL development • By altering chromatin in CD8+ T cells, IL-10R blockade disrupts NFAT:AP-1 cooperativity • IL-10R loss correlates with T cell exhaustion and poor survival of cancer patients T cell exhaustion limits anti-tumor immunity and responses to immunotherapy. Using a model of chronic lymphocytic leukemia, Hanna, Llaó-Cid, et al. reveal that the balance between PD-1hi, exhausted CD8+ T cells and functional PD-1int CD8+ T cells that are associated with tumor progression or tumor control, respectively, is regulated by cell-intrinsic IL-10R signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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