肿瘤细胞中DUSP1调控髓源抑制细胞扩增及其在结肠癌免疫耐受中的作用和机制分析

Myeloid-derived suppressor cells (MDSCs) contribute to the negative regulation of anti-tumor immunity and immune tolerance. The key signaling molecules in tumor may not only provide a cell-intrinsic regulation for tumor cells, but also regulate the composition pattern of immune cells and related factors in tumor microenvironment. However, the molecular mechanisms that are responsible for the tumor cell-mediated modulation of expansion and function of MDSCs need to be elucidated. The dual-specificity phosphatase-1 (DUSP1) plays a role in the development of certain tumors. Our previous studies have shown that DUSP1 overexpression in the colon cancer cells substantially decreased the ratio of MDSCs and increased production of effector cytokines from CD4+T, CD8+T and γδT cells in the tumor microenvironment. We also observed the DUSP1 overexpression regulated the induction of tumor-derived factors. In the present study, we will investigate the effect of DUSP1 in colon cancer cells on the expantion and function of MDSCs，mainly including the following three aspects: 1.The effect of DUSP1 on the accumulation and suppressive function of MDSCs in colorectal carcinoma. 2.The mechanisms underlying the DUSP1-mediated modulation of MDSCs. 3.The clinical relevance of DUSP1 expression and MDSCs accumulation and function in human colorectal carcinoma. The study will improve our understanding of how tumor immune tolerance enviroment is established and contributes to the design of new strategies targeting MDSCs for cancer immune therapy.

髓源抑制细胞(MDSCs)在肿瘤免疫耐受形成中起重要促进作用。肿瘤细胞中关键信号分子，除调节肿瘤细胞功能外，也调控肿瘤微环境免疫细胞的格局。但目前关于肿瘤细胞内信号分子影响肿瘤微环境MDSCs扩增和功能的机制未知。双特异性磷酸酶DUSP1参与调控肿瘤发展。我们前期研究表明，结肠癌肿瘤细胞中表达DUSP1导致肿瘤微环境中MDSCs比率下降，效应细胞产生效应分子增加。另外，DUSP1可以调控肿瘤源性因子的产生。因此，我们认为DUSP1在调控结肠癌肿瘤微环境中MDSCs功能中发挥重要作用。本课题将从三方面进行：1.结肠癌肿瘤细胞中DUSP1对MDSCs分布和抑制功能的调控；2.DUSP1调控MDSCs扩增和功能的机制；3.人结肠癌肿瘤标本中DUSP1表达与MDSCs分布和功能的关系。该研究将为阐明肿瘤免疫耐受形成机制和设计以MDSCs为靶点的新肿瘤免疫治疗策略提供依据和思路。

肿瘤细胞中关键信号分子，除了对肿瘤细胞自身有作用，也调控肿瘤微环境的格局。髓源抑制细胞(MDSCs)在肿瘤免疫耐受形成中起重要促进作用。双特异性磷酸酶DUSP1参与调控肿瘤发展。我们的研究主要围绕两部分开展：1.结肠癌肿瘤细胞中DUSP1对MDSCs分布、扩增和抑制功能的调控及其机制；2. DUSP1对肿瘤细胞衰老影响。在本项目的支持下，我们发现，DUSP1下调结肠癌肿瘤组织内MDSCs比率，诱导结肠癌肿瘤内CD8+T，CD4+ T和γδT细胞IFN-γ产生增加。DUSP1调控结肠癌细胞多种与MDSCs趋化、扩增和功能相关的肿瘤源性因子表达。包括下调IL-6, CXCL12, CCL5, SCF, TGF-β, VEGFa, VEGFb, PDGF, PTGS2, PTGES和PTGES2的表达。进一步实验证明，DUSP1下调MDSCs的抑制功能，下调MDSCs抑制性分子PD-L1和IL-10的表达。另一方面，由于肿瘤细胞的衰老可以调节自身增殖或是影响免疫监视功能，从而影响肿瘤抑制环境。本项目进一步探讨了DUSP1对肿瘤细胞衰老的影响。我们发现DUSP1可以抑制肿瘤细胞的增殖，促进肿瘤细胞的衰老，并且DUSP1诱导的衰老与p53/p21和p16/Rb信号通路无关。进一步研究表明，DUSP1通过下调Cyclin D1，促进肿瘤细胞的衰老，抑制肿瘤细胞的生长。更为有趣的是，与Doxorubicin诱导的细胞衰老相比，DUSP1并不上调衰老相关的IL-6和IL-8等相关因子的表达。该研究将为阐明肿瘤免疫耐受形成机制和设计以MDSCs和DUSP1为靶点的新肿瘤免疫治疗策略提供依据和思路。