Stat3 underlies IL-23-mediated suppression of anti-tumor immunity

4199

IL-23 and IL-12 are closely related cytokines. However, whereas IL-12 is a strong anti-tumor immune mediator and hardly detectable in tumor, IL-23 suppresses anti-tumor immunity and is highly expressed in cancer. The mechanism(s) allowing elevated expression of IL-23 and suppression of IL-12 in tumors remains undefined. We have shown previously that Stat3 not only promotes production of multiple immunosuppressive factors, but also inhibits expression of many immunostimulatory molecules including IL-12. In this study, we determine if the immunosuppressive effects of Stat3 and IL-23 are coordinated. We found that the expression of p19 subunit of IL-23 in B16 melanoma is mediated by Stat3. IL-23 expression is most pronounced in tumor stromal Gr1⁺ immature myeloid cells and macrophages, while ablating Stat3 leads to drastic increase in IL-12 expression by dendritic cells (DCs). The molecular mechanism defining IL-12 and IL-23 expression profile involves an intricate crosstalk between Stat3 and NF-κB signaling pathways. Stat3 and NF-κB/p65 synergistically enhance IL-23 expression by directly binding to the IL-23/p19 promoter. In contrast, Stat3 signaling in DCs reduces NF-κB/c-Rel binding activity to IL-12/p35. We further show that IL-23 can activate Stat3 in macrophages and DCs, upregulating several immunosuppressive factors such as IL-10 and IL-23 while inhibiting IL-12. In addition, IL-23 stimulates Stat3 activity in tumor T regulatory cells (Tregs). Blocking IL-23 signaling by an antibody against IL-23 receptor in vivo enhances immunostimulatory function of DCs while reducing expression of suppressive mediators by Tregs, thereby significantly reducing B16 melanoma growth. Our findings demonstrate that Stat3 is critical for IL-23 overexpression in tumor and IL-23 in turn helps to propagate immunosuppressive effects of Stat3 activity from tumor stromal myeloid cells to DCs and Tregs. Targeting Stat3-IL-23 within the tumor microenvironment may therefore overcome tumor immune evasion, offering a potentially exciting opportunity for cancer immunotherapy.
 This work was supported by the National Institute of Health grants and the Harry J. Lloyd Charitable Trust Award to Hua Yu.