The role of CCR2 in prognosis of patients with endometrial cancer and tumor microenvironment remodeling

Tumor microenvironment (TME) plays a core role in the genesis and progress of endometrial carcinoma (EC). The immune system, a crucial element of TME, functions in various immune cells. In this paper, we have tried to evaluate the prognosis in EC patients by the status of TME. The ESTIMATE algorithm was implemented to computer the number of immune and stromal components in EC tissues from the Cancer Genome Atlas dataset. The CIBERSORT algorithm was employed to assess the proportion of tumor-infiltrating immune cells in EC tissues, which were quantified as Stromal score and Immune score. After the construction of protein–protein interaction network, cell–cell chemokine receptor 2 (CCR2) was identified as a potential predictive element for EC. Further analysis indicated that a higher expression of CCR2 in EC patients was correlated with a better prognosis and a prolonged disease-free survival. According to the transcript level of CCR2, samples were separated into low- and high-expression groups. Gene Set Enrichment Analysis unveiled that metabolism-related pathways were mostly abundant in groups with high-expression, the other one was primarily correlated to immune-related activities. We figured out that some immune cells were positively related to CCR2, suggesting that CCR2 might serve as the immune-dominant status of TME, which was verified by qRT-PCR and HPA analysis in transcriptome and protein level, respectively. Also, CCR2 showed high correlation with immune modulators and chemokine signaling pathway. Thus, the level of CCR2 might have a prognostic value for EC patients, which provides a novel insight for therapeutic strategies of EC.

肿瘤微环境（Tumor Microenvironment, TME）在子宫内膜癌（Endometrial Carcinoma, EC）的发生与进展中发挥核心作用。作为TME的关键组成部分，免疫系统由多种免疫细胞共同发挥功能。本研究尝试通过TME状态评估子宫内膜癌患者的预后情况。研究采用ESTIMATE算法，对癌症基因组图谱数据集（Cancer Genome Atlas Dataset）中子宫内膜癌组织的免疫与基质成分含量进行计算；并运用CIBERSORT算法评估子宫内膜癌组织中肿瘤浸润免疫细胞的占比，将其量化为基质评分（Stromal score）与免疫评分（Immune score）。在构建蛋白质-蛋白质相互作用网络后，本研究鉴定出细胞间趋化因子受体2（CC chemokine receptor 2, CCR2）可作为子宫内膜癌的潜在预测因子。进一步分析表明，子宫内膜癌患者体内CCR2的高表达与更佳预后及更长的无病生存期显著相关。研究人员依据CCR2的转录水平将样本分为高表达组与低表达组。基因集富集分析（Gene Set Enrichment Analysis, GSEA）结果显示，高表达组主要富集于代谢相关通路，而低表达组则主要与免疫相关活动相关。本研究发现部分免疫细胞与CCR2呈正相关，提示CCR2或可作为TME免疫主导状态的标志物，该结论分别通过转录组层面的qRT-PCR（Quantitative Reverse Transcription Polymerase Chain Reaction）与蛋白质层面的人类蛋白质图谱（Human Protein Atlas, HPA）分析得到验证。此外，CCR2与免疫调节剂及趋化因子信号通路高度相关。综上，CCR2的表达水平或可作为子宫内膜癌患者的预后评估指标，为子宫内膜癌的治疗策略提供全新研究视角。