结直肠癌肿瘤微环境中G-MDSCs通过外泌体调控M-MDSCs向TAMs分化的机制研究

The recruitment of myeloid-derived suppressor cells (MDSCs) and differentiation of tumor-associated macrophages (TAMs) are the major factors contributing to tumor progression. However, the relationship between MDSCs recruitment and TAMs differentiation has not yet been clearly understood. It has been reported that monocytic MDSC (M-MDSCs) could differentiate into TAMs in tumor tissue. Our previous study on granulocytic MDSC (G-MDSCs) from colorectal cancer tissue showed that G-MDSCs derived exosomes (GM-Exo) promoted the differentiation of M-MDSCs into TAMs. Thus, we put forward the hypothesis that G-MDSCs may promote the differentiation of M-MDSCs into TAMs by the exosomes secretion in the tumor microenvironment of colorectal cancer, which facilitate colorectal cancer progression. In this project, we will identify the key functional components of GM-Exo which promote M-MDSCs differentiation into TAMs and reveal the related mechanism. Then, we will verify the roles of GM-Exo and related components in the differentiation of M-MDSCs into TAMs in mouse model of colorectal cancer. Our study may help clarify the relationship among G-MDSCs, M-MDSCs and TAMs and the mechanism of TAMs differentiation from M-MDSCs, which may provide scientific basis for the immunotherapy of colorectal cancer.

髓源性抑制细胞（MDSCs）聚集和肿瘤相关巨噬细胞（TAMs）分化是影响肿瘤进展的关键因素，然而二者的关系尚未明确。现有文献报道肿瘤局部的单核细胞样MDSC（M-MDSCs）可以分化为TAMs。申请人前期研究发现，结直肠肿瘤组织粒细胞样MDSC（G-MDSCs）分泌的外泌体（GM-Exo）促进M-MDSCs分化为TAMs。据此推测：结直肠癌肿瘤微环境中G-MDSCs通过外泌体促进M-MDSCs分化为TAMs，进而促进结直肠癌进程。本项目拟进一步阐明GM-Exo中促进M-MDSCs分化为TAMs的功能分子及其作用机制；并通过结直肠癌小鼠模型验证GM-Exo及其功能分子在M-MDSCs向TAMs分化中的作用。本研究将有助于阐明G-MDSCs、M-MDSCs和TAMs之间的关系及M-MDSCs向TAMs分化的机制，为结直肠癌的免疫治疗提供理论依据。

背景：在炎症性肠病微环境中，MDSC的转分化和M2巨噬细胞的积累对于结肠炎向癌症的转变至关重要。研究结肠炎-癌症转化过程中髓源性抑制细胞(MDSCs)和M2巨噬细胞之间的串扰和潜在机制为结肠炎相关癌症(CAC)治疗的预防提供方向和理论基础。方法：采用细胞实验、免疫荧光、流式细胞术、小干扰RNA等研究粒细胞性MDSCs (G-MDSCs)或外泌体(Exo)调节单核细胞性MDSCs (M-MDSCs)向M2巨噬细胞分化的体外作用和潜在机制。利用DSS诱导的结肠炎和CAC小鼠模型，研究抗IL-6抗体和STAT3抑制剂的体内疗效和机制。结果：G-MDSC通过exosomal miR-93-5p通过抑制STAT3活性促进M-MDSC向M2巨噬细胞。IL-6促进miR-93-5p在G-MDSC外泌体(GM-Exo)中的富集。早期使用IL-6抗体可增强STAT3抑制剂对CAC的作用。结论：IL-6促进G-MDSC exosomal miR-93-5p分泌调控调控M-MDSC向M2巨噬细胞分化。将STAT3抑制剂与抑制il -6介导的G-MDSC外泌体miR-93-5p产生的策略相结合，有利于CAC的防治。