IL-6/STAT3 signaling impaired induction of cancer-antigen specific T cells via down-regulation of dendritic cells in tumor microenvironment.

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590 Background: Immunosuppression in tumor microenvironments is a critical issue for cancer immunotherapy. Recently, the effectiveness of immuno-check point therapy has been reported on various types of solid tumors. But, the effectiveness in colorectal cancer was poor compared to other cancers, such as melanoma and renal cell carcinoma. Correct regulation of dendritic cell (DC) function in tumors is important for inducing anti-tumor immunity. We have been demonstrated that IL-6 inhibits antigen presentation by DCs through STAT3 activation in tumor-bearing mice. In this study, we focused on the role of the IL-6/STAT3 signaling cascade in human DCs. Methods: Both IL-6 and pSTAT3 expressions in tumor sites of colorectal cancers was verified by immunohistostaining. CD11b+CD11c+DCs in cancer tissues and PBMCs were isolated by fluorescence-activated cell sorting system and investigated about the surface molecules such as HLA-DR, T cell stimulating ability, and effector gene expression levels. Moreover, we investigated influence of IL-6/STAT3 signaling in human DCs in vitro. Results: The results of IHC revealed that IL-6 was preferentially produced by cancer-associated fibroblasts and immune cells in the tissues of colorectal cancers. In addition, it was confirmed that STAT3 was activated in tumor-infiltrating immune cells. Tumor infiltrating CD11b+CD11c+ DCs highly induced IL-6 gene, down-regulated surface expression of HLA-DR, and attenuated T cell stimulating ability. In vitro experiments showed that IL-6-mediated STAT3 activation reduced surface expression of HLA-DR. COX2, cathepsin L (CTSL), and arginase activity were are involved in the IL-6-mediated down-regulation of surface expression levels of HLA-DR expression levels on DCs. Gene expressions of CTSL, ARG1 as well as IL6 in tumor infiltrating CD11b+CD11c+DCs were much higher than those of PBMCs. Conclusions: IL-6-mediated STAT3 activation inhibits functional maturation of DCs, causing suppression of anti-tumor immunity in colorectal cancer. Therefore, inhibition of the IL-6/STAT3 signaling pathway could be a promising strategy for improving immunotherapies for colorectal cancer patients.