以髓样抑制性细胞为靶点的香菇多糖MPSSS联合IL4抗肿瘤机制研究

The immunologic negative regulation status in tumor microenvironment is one of the important reasons of tumor drug resistance, during which myeloid derived suppressor cells (MDSCs) is the main part to maintain immunologic negative status. We found MPSSS, one of Lentinus edodes polysaccharide, had antitumor effect in vivo. MPSSS induced MDSC diffentitation into M1-like macrophage, and increased the MHC-Ⅱ expression level on the surface of MDSC. Some cytokine, such as IL4, is able to induce MDSCs to terminal differentiation into DC, which is helpful for tumor antigen presentation. However, the IL4 receptor of the MDSC surface decreased at the late stage of tumor growth (18-20 day), so the IL4 lose its effect on tumor. The reason was that the IL4 receptor decreased on the surface of MDSC. The project is focus on the molecular mechanism and signal pathway, and study the cooperation effect between MPSSS and IL4 on MDSC. MPSSS will promote MDSC differentiate into M1-like macropahge, and IL4 will them into DC. The effect of MPSSS on MDSC will enhanced the effec of IL4, and the cooperation effect will promote the therapy effect on tumore. The results will provide novel molecular and project for clinical antitumor treatment.

肿瘤微环境中的免疫负调控状态是导致肿瘤免疫逃逸的重要原因，其中髓样抑制性细胞(MDSC)是维持免疫负调控的重要细胞成分。本项目组前期发现香菇多糖组分MPSSS具有较好的体内抗肿瘤效应，MPSSS可诱导MDSC细胞分化为M1样巨噬细胞，并引起MDSC分子表面MHC-II分子上调。本项目组前期还发现IL4早期应用可促进MDSC成熟分化为树突状细胞，并可引起肿瘤消退，但是晚期IL4促MDSC成熟分化效应消失，究其原因，MDSC表明IL4受体下调。本项目拟研究MPSSS诱导MDSC分化的分子机制及其具体的信号通路，并研究MPSSS与IL4联用能否产生协同抗肿瘤效应，即MPSSS促进MDSC成熟分化为M1巨噬细胞，IL4促进MDSC转化为DC，利用MPSSS促MDSC分化效应弥补IL4对晚期肿瘤MDSC效应不佳的不足，以提高肿瘤治疗效果，预期成果将为抗肿瘤研究提供新的候选分子和新方案。

髓样抑制性细胞是重要的免疫负调控细胞，目前已作为重要的肿瘤治疗靶点。本研究联合香菇多糖MPSSS和IL4，开展了对MDSC的效应机制研究，研究方法为构建小鼠荷瘤模型，荷瘤3周后制备脾细胞单细胞悬液，体外采用MPSSS和IL4对MDSC进行联合作用，2天后进行流式细胞学分析，随后研究重点对MPSSS对MDSC分化的信号通路进行了研究。结果显示MPSSS和IL4分别诱导MDSC向巨噬细胞和DC细胞方向分化，效应不成叠加关系，而呈现相对独立的状态。清道夫受体是MPSSS作用于MDSC的途径之一，可以引起细胞内JNK信号通路的激活，进而发挥下游的促分化作用。本研究结果的取得，为深入探讨香菇多糖作用于MDSC的信号通路提供了依据，为提升临床以MDSC为靶点的抗肿瘤研究提出了线索。