Interleukin-10 Attenuate Tumor Growth by Inhibiting Interleukin-6/Signal transducer and activator of transcription 3 Axis on Myeloid-Derived Suppressor Cells

Abstract

Abstract Interleukin-10 (IL-10) is a well-characterized anti-inflammatory cytokine, but its role in anti-cancer immunity is still controversial. When IL-10 knockout (IL-10−/−) mice were subcutaneously injected with TC-1 cancer cells expressing HPV E6 and E7 proteins, tumor growth was accelerated in IL-10−/− mice than wild type (WT) mice. Interestingly, the production of interleukin-6 (IL-6) was significantly increased in IL-10−/− mice than in WT mice. The blockade of IL-6 by systemic administration of anti-IL-6 receptor (IL-6R) monoclonal antibody (mAb) inhibited the tumor growth, and inhibited the generation of myeloid-derived suppressor cells (MDSCs) which were increased in IL-10 deficiency. MDSCs and tumor cells from IL-10−/− mice had increased phosphorylated-signal transducer and activator of transcription 3 (p-STAT3) level and the treatment of mice with STAT3 inhibitor, S3I reduced the tumor growth and inhibited the expansion of MDSCs. Accordingly, S3I also reduced tumor necrosis factor-a (TNF-a) and IL-6 in tumor. Although S3I treatment relieved T cells from suppression by reducing the number of MDSCs, it seems that the proportion of MDSCs having M2 macrophage phenotype was increased among myeloid cells since the transcription of Arg1, Mgl1, Mgl2, and, Fizz1, were significantly increased and the expression of some suppressive functional mediators of MDSCs, including Arg1 and iNOS was up-regulated. Combined treatment of anti-IL-6 mAb and S3I could further suppress the generation of M2-type MDSC and regulate immunosuppressive function of MDSCs, and finally inhibited tumor growth more efficaciously. These results suggested that combined inhibition of IL-6 and STAT3 could be a potential candidate as an anti-cancer strategy.