ena-STUDY-DKFZ HEIDELBERG-30-08-2021-09:25:35:558-1394
IL-10 receptor signaling protects CD8+ T-cells from activation-induced exhaustion and prevents tumor immune escape
Chronic antigenic stimulation in tumors drives T-cells into terminal differentiation or “exhaustion”. Here, we explore microenvironmental signals regulating this process and report on an unexpected mechanism by which IL-10 prevents activation-induced exhaustion of tumor-reactive T-cells in chronic lymphocytic leukemia (CLL). We identified a subset of CD8 + effector T-cells with high PD-1 expression and exhausted phenotype that accumulated in secondary lymphoid organs of CLL patients during disease progression. These T-cells were transcriptionally distinct from less differentiated cells with intermediate PD-1 expression which showed a higher functional competence upon restimulation. The balance between these two CD8 + T-cell subtypes was regulated by IL-10R/STAT3 signaling. Blocking IL-10 receptor altered chromatin accessibility and disrupted the cooperativity of NFAT and AP-1 in CD8 + T-cells. These changes were accompanied by a dramatic loss of the PD-1 int subset and an accumulation of dysfunctional PD-1 hi cells, leading to a significantly enhanced tumor development. We conclude that the T-cell mediated control of CLL is compromised by IL-10 receptor blockade or genetic depletion of Il10rb or Stat3 . Furthermore, loss of IL-10R/STAT3 signaling correlated with CD8 + T-cell terminal differentiation and poor survival in cancer patients. Taken together, our data demonstrate a central role of IL-10R/STAT3 signaling for preventing CD8 + T-cell exhaustion, which could be exploited for improving immunotherapy.
Chronic antigenic stimulation in tumors drives T-cells into terminal differentiation or “exhaustion”. Here, we explore microenvironmental signals regulating this process and report on an unexpected mechanism by which IL-10 prevents activation-induced exhaustion of tumor-reactive T-cells in chronic lymphocytic leukemia (CLL). We identified a subset of CD8 + effector T-cells with high PD-1 expression and exhausted phenotype that accumulated in secondary lymphoid organs of CLL patients during disease progression. These T-cells were transcriptionally distinct from less differentiated cells with intermediate PD-1 expression which showed a higher functional competence upon restimulation. The balance between these two CD8 + T-cell subtypes was regulated by IL-10R/STAT3 signaling. Blocking IL-10 receptor altered chromatin accessibility and disrupted the cooperativity of NFAT and AP-1 in CD8 + T-cells. These changes were accompanied by a dramatic loss of the PD-1 int subset and an accumulation of dysfunctional PD-1 hi cells, leading to a significantly enhanced tumor development. We conclude that the T-cell mediated control of CLL is compromised by IL-10 receptor blockade or genetic depletion of Il10rb or Stat3 . Furthermore, loss of IL-10R/STAT3 signaling correlated with CD8 + T-cell terminal differentiation and poor survival in cancer patients. Taken together, our data demonstrate a central role of IL-10R/STAT3 signaling for preventing CD8 + T-cell exhaustion, which could be exploited for improving immunotherapy.