STAT3 regulates CD8+ T cell differentiation and functions in cancer [RNA-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. Overall design: RNA-seq of WT and Stat3-/- OT-I cells from B16-OVA tumors at about day 16 post inoculation