ID1诱导肿瘤相关巨噬细胞极化促进结肠癌干细胞特性和肿瘤免疫逃逸的作用和机制

肿瘤细胞与周围免疫细胞、成纤维细胞等共同构成了复杂的肿瘤微环境。这些组分交互作用共同促进肿瘤恶性进展。本项目前期工作证实，DNA结合抑制因子ID1在结肠癌肿瘤局部巨噬细胞中高表达，增强巨噬细胞促肿瘤表型。此外，我们发现免疫效应分子IFNγ诱导肿瘤相关巨噬细胞中ID1表达增高。基于上述研究基础我们提出本项目研究假说，即ID1参与诱导和维持肿瘤相关巨噬细胞的促肿瘤表型；IFNγ诱导巨噬细胞ID1表达增高可能是结肠癌免疫治疗不敏感的原因之一。本项目将从分子、细胞、基因敲除动物等多层次探寻IFNγ诱导巨噬细胞ID1高表达的分子机制；从肿瘤相关巨噬细胞调节肿瘤干细胞特性和诱导抑制性肿瘤免疫微环境两方面解析ID1维持巨噬细胞促肿瘤表型的作用和机制。在此基础上寻找靶向抑制ID1的治疗性多肽分子，探索改善结肠癌免疫治疗效果的新策略。

Tumor cells interact closely with the surrounding immune cells and stromal cells, which together form the complicated tumor microenvironment. These cells crosstalk with each other and promote tumor progression synergistically. In our previous study, Inhibitor of DNA binding 1 (ID1) was found to be highly expressed in macrophages infiltrated in colon cancer tissues. Data from the ID1-myeloid specific knockout mice showed that ID1 positively regulated the pro-tumor phenotype of macrophage. In addition, ID1 was found to be upregulated in IFNγ-treated macrophages. Based on these observations, we provide our hypothesis that the pro-tumor phenotype of macrophage induced by ID1 participates in the maintenance of colon cancer stemness and immune evasion. Moreover, IFNγ-induced ID1 expression in macrophage may result in the low response of most colorectal cancer to immunotherapy. We’ll pursuit the potential roles and mechanisms of ID1 in the regulation of macrophage polarization by using molecular & cellular technologies and animal models. We'll also explore the therapeutic strategy against colon cancer through targeting ID1 expression and function. Our proposed studies may not only provide deep insights of crosstalk between tumor microenvironment and tumor cell intrinsic properties in the promotion of colorectal carcinogenesis and progression, but also provide clues and strategies to enhance the efficacy of immunotherapy against colon cancer.