Role Of IL-27in Tumor Immunity And Evaluation The Application Of Self-assembled Nanofibers Of Taxol In Tumor Therapy

Cancer is a major threat to human health, thus studies focusing on revealing the interaction between cancer cells and host immune system and developing novel antitumor drugs are with great value. Tumor development is tightly dictated by tumor microenvironment. Cytokine is an important component of tumor microenvironment, so it is urgent to define the role of different cytokines in tumor immunity. Interleukin-27(IL-27), consisted of Epstein-Barr virus-induced gene3(EBI3) and a p28subunit, is a newly discovered heterodimeric cytokine belongs to the IL-12family. To study the biological function of IL-27in innate and adaptive tumor immunity, the IL-27p28flox/flox mice generated in our lab were used. These mice had been crossed with EⅡα-Cre mice and CD11c/Itgax-Cre mice to delete IL-27p28alleles in nearly all tissues (EⅡα-p28f/f mice) and specially in dendritic cells (Itgax-p28f/f mice). We have demonstrated that IL-27is critical in protective immune responses against methyl-cholanthrene induced fibrosarcoma and transplanted B16melanoma, and that dendritic cells are its primary source. IL-27is required for shaping the tumor microenvironment by inducing CXCL-10expression in myeloid derived suppressor cells (MDSC) and regulating IL-12production from dendritic cells (DC), leading to the recruitment and functional maintenance of tumor infiltrating NK and NKT cells, respectively. NK and NKT cells are important tumor kiiling cells which produce large amount of antitumor factor IFN-γ. We also studied the impact of IL-27on adaptive tumor immune response. Surprisingly, IL-27was found to be critical for the enrichment of tumor promoting regulatory T cells (Tregs) in tumor tissues. In the absence of IL-27, Tregs were significantly decreased in tumors. Further studies revealed that IL-27promoted the expression of CCL22which is established to mediate the recruitment of peripheral Tregs into tumors. Tumor associated DCs were identified as the major source of CCL22in tumor sites, and IL-27could induce CCL22expression in an IL-27R dependent manner. Correlated with decreased number of Tregs, tumor infiltrating CD4T cells were found to produce much more IFN-γ in IL-27p28KO mice, which highlighted the physiological importance of Tregs in suppressing antitumor immune response. In summary, we establish the physiological function and underlying mechanisms of endogenous IL-27in tumor immunology for the first time. We also made a lot of efforts on developing novel antitumor drugs. We designed and prepared a novel self assembled Taxol hydrogels, which could be administrated directly into solid tumors to dramatically inhibit their growth. Besides the improved therapeutic effect compared to the clinically used Taxol, the concentration of taxol in blood was low due to the local administration of taxol hydrogels, which greatly enhanced the tolerance dosage of mice to taxol and might reduce side effects of taxol during chemotherapy. Our observations suggested that our Taxol hydrogel would have great practical application potential. Overall, current report would provide great insights into developing novel tumor therapeutic strategies.