Hanna and Llaó-Cid et al. identified subsets of CD8+ T cells with either intermediate or high PD-1 expression in CLL patients and a mouse model. PD-1int cells expressed TCF-1 and were functionally competent, whereas PD-1hi cells represented a functionally impaired exhausted T cell population. Genetic and pharmacological inhibition of IL-10R–STAT3 signaling led to accumulation of PD-1hi CD8+ T cells, altered chromatin and reduced AP-1 DNA accessibility, impaired CD8+ T cell proliferation, and accelerated CLL progression in vivo. In patients with cancer, loss of IL-10R–STAT3 signaling correlated with CD8+ T cell exhaustion and poor survival.
Contributed by Shishir Pant
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-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(int) 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(int) TCF-1(+) CD8(+) T cells is regulated by cell-intrinsic IL-10R signaling, with implications for immunotherapy.