STAT3 regulates CD8+ T cell differentiation and functions in cancer [ChIP-seq]

In cancer, persistent antigens drive CD8+ T cell differentiation into exhausted progenitor (Texprog) and terminally exhausted (Texterm) cells. However, how the extrinsic and intrinsic regulatory mechanisms cooperate during this process still remain not well understood. Here, we found STAT3 signaling plays essential roles in promoting intra-tumor Texterm cell development, by enhancing their effector functions and survival, which results in better tumor control. In tumor microenvironments, STAT3 is predominantly activated by IL-10 and IL-21, but not IL-6. Besides, STAT3 also plays critical roles in the development and function of terminally differentiated effector CD8+ T cells in acute infection. Mechanistically, STAT3 transcriptionally promotes the expression of effector function-related genes, while suppresses those expressed by progenitor Tex subset. Moreover, STAT3 functions in collaboration with BATF and IRF4 to mediate chromatin activation at effector gene loci. Thus, we have elucidated the roles of STAT3 signaling in terminally differentiated CD8+ T cell development, especially in cancer, which benefits developing more effective immunotherapies against tumor. FACS sorted naïve CD8+ T cells were activated with the plate-bound anti-CD3 and anti-CD28 for three days. For pSTAT3 ChIP-seq, the activated WT CD8+ T cells were cultured at 37 ℃ for 30 minutes in fresh medium with 10ng/ml IL-6, 10ng/ml IL-10 or 10ng/ml IL-21. For H3K27ac ChIP-seq, the activated WT and Stat3-/- CD8+ T cells were stimulated by 10ng/ml IL-10 for another three days. Chromatin from 1x10^7 live cells was used for each ChIP experiment. 7.5µg anti-pSTAT3(Y705) antibody or 1µg anti-H3K27ac antibody were used.