CAFs分泌CXCL12调控MDSCs活化和功能促进子宫内膜癌进展的机制研究

Myeloid-derived suppressor cells (MDSCs) infiltration is believed to play an essential role in endometrial cancer (EC) carcinogenesis and progression. However, the mechanism of CAFs in EC progression is unclear. The applicant have published research (J Hematol Oncol, IF:6.3) confirmed that CAFs secreted soluble CXCL12 more than normal fibroblasts, CXCL12 not only promoted EC progession through CXCL12/CXCR4 axis, but also positively correlated with MDSCs infiltration. CXCL12 could promote the proliferation of MDSCs. However, there are few studies about how CXCL12 regulates the activation and function of MDSCs to promote the progression of EC. This project will explore the mechanism of EC in three aspects. First, we plan to detect the ratio, phenotype and function of MDSCs and other immune cells subsets in peripheral blood and tumor tissue, and then analyze the correlation between them and CXCL12, also between them and poor biological behavior of EC. Second, we will observed the effect of CXCL12 secreted by CAFs on the activation state and function of MDSCs and its possible mechanism in vitro.Third, we will establish a mouse model of EC, to explore whether CXCL12 affected the number and function of immune cells subsets through MDSCs to promote the progress of EC in mice. This study can help to improve the understanding of the mechanism of EC progression, and providing theoretical basis for EC immunotherapy.

MDSCs浸润具有促进肿瘤发生发展的作用，但在子宫内膜癌(EC)中机制仍不清。申请人已发表的研究(J Hematol Oncol, IF:6.3)发现CAFs分泌的CXCL12显著增多，CXCL12除通过CXCL12/CXCR4轴促进EC的进展外，还与MDSCs浸润呈正相关，且CXCL12可促进MDSCs增殖，然而CXCL12如何调控MDSCs活化和功能改变促进EC进展的研究甚少。本课题拟从：①临床观察外周血及肿瘤组织标本中MDSCs细胞和免疫细胞亚群细胞比例、表型、功能变化，与CXCL12表达相关性及与EC临床病理特征和预后的关系；②体外实验观察CAFs分泌的CXCL12对MDSCs活化状态和功能的影响及其可能机制；③体内实验探索CXCL12是否通过MDSCs影响各免疫细胞亚群数量及功能，促进小鼠EC的进展。本研究有助于提高对EC进展机制的认识，为EC的免疫治疗提供理论依据。

子宫内膜癌（EC）是女性生殖系统最常见恶性肿瘤。EC的发生、发展不仅涉及肿瘤细胞本身，还与肿瘤微环境密切相关。EC的组织学特征是基质成分包绕癌细胞占据了肿瘤的相当一部分体积，这其中的癌旁成纤维细胞（CAFs）和髓系抑制性细胞（MDSCs）介导了EC的免疫逃逸。CAFs分泌的CXC趋化因子配体12(CXCL12)显著增多，与MDSCs浸润呈正相关，然而CXCL12如何调控MDSCs活化和功能改变促进EC进展的机制尚不明确。本课题从三方面研究：①临床研究发现Mo-MDSCs细胞和PMN-MDSCs细胞的比例在EC患者外周血中显著升高，尤其是Mo-MDSCs细胞，NK细胞、DC细胞、TAM细胞和Th1细胞的比例在EC患者外周血降低，Th2细胞、Th17细胞、Treg细胞的比例在EC患者外周血中显著升高。EC患者组织中MDSCs细胞比例升高与CXCL12表达升高呈正相关，与患者深肌层浸润和淋巴结转移呈正相关。②体外研究明确了CXCL12对MDSCs细胞具有趋化作用，无增殖和凋亡作用，对MDSCs分化表型的变化无影响；CXCL12可增加MDSCs的ROS和H2O2的表达，具有活化MDSCs的功能，抑制CD4+ T淋巴细胞和CD8+ T淋巴细胞亚群的比例，进一步研究发现CXCL12可增强MDSCs内的p-STAT3和p-JNK的蛋白表达，进而激活STAT3/JNK信号通路促进MDSCs的活化和功能表达，形成EC免疫抑制微环境。③动物实验发现CXCL12可促进小鼠EC移植瘤的生长，可能的机制是CXCL12可激活MDSCs细胞内的STAT3/JNK信号通路促进其活化和免疫抑制功能。本课题执行期间发表文章8篇，其中SCI收录4篇，科技核心收录论文4篇，协助培养毕业博士生1名，参加国内学术会议交流6次，圆满达到预期效果。本课题为免疫微环境在EC进展中的机制提供新的认识，为EC免疫治疗提供理论依据，具有重要的转化医学意义。