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

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(i)(nt) 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(i)(nt) TCF-1(+) CD8(+) T cells is regulated by cell-intrinsic IL-10R signaling, with implications for immunotherapy.

Automated summary

The balance between PD-1(hi) exhausted CD8(+) T cells and functional PD-1(i)(nt) TCF-1(+) CD8(+) T cells is regulated by cell-intrinsic IL-10R signaling, which impacts the immune response and tumor progression. Low levels of IL-10 expression or loss of IL-10R-STAT3 signaling are associated with increased frequencies of exhausted CD8(+) T cells and poor survival in CLL and breast cancer patients.