Table_5_Estrogen Receptor Downregulates Expression of PD-1/PD-L1 and Infiltration of CD8+ T Cells by Inhibiting IL-17 Signaling Transduction in Breast Cancer.XLSX

Background: The relationship between the interleukin 17 (IL-17) family of cytokines and breast cancer has been widely studied in recent years. Many studies have revealed increased levels of the cytokine IL-17A in estrogen receptor (ER)-negative or triple-negative breast cancer. Upregulation of IL-17A signaling is associated with increased expression of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) in breast cancer with low ER expression and may elevate the infiltration of CD8+ T cells in tumor tissue. This study aims to determine whether ER downregulates the expression of PD-1/PD-L1, reduces the infiltration of CD8+ T cells, and affects the immune microenvironment by decreasing T-helper 17 (Th17) cell infiltration and inhibiting IL-17 signaling in breast cancer.
Methods: Samples in The Cancer Genome Atlas Breast Cancer dataset were grouped by ER status and the PAM50 intrinsic subtype. The expression of IL-17 family cytokines and Th17 cell signature cytokines were compared between groups. IL-17 signaling pathway-related genes that were differentially expressed according to the ER level were identified. The PD-1 and PD-L1 levels were compared between breast cancer samples with different ER statuses and IL-17A/IL-17F expression levels. Correlation analyses of the expression of PD-1/PD-L1 and IL-17 signaling pathway-related genes were performed. The associations of the expression of IL-17 signaling pathway-related genes with the immune microenvironment were investigated.
Results: High levels of ER decreased the expression of IL-17A, IL-17C, and IL-17F but increased the expression of IL-17E (IL25), which acts as a suppressor of IL-17 signaling. The expression levels of Th17 cell signature cytokines were significantly increased in ER-negative breast cancer. The expression levels of genes encoding downstream products of IL-17A/IL-17F signaling were downregulated in breast cancer with high ER expression. Increased expression of PD-1/PD-L1 was associated with ER-negative status, IL-17A-positive status, IL-17F-positive status, and upregulation of IL-17 signaling pathway-related genes in breast cancer. Enhanced IL-17 signal transduction was associated with the elevation of CD8+ T cell infiltration and variation of the immune microenvironment of breast cancer.
Conclusion: High estrogen receptor levels decrease PD-1/PD-L1 expression and CD8+ T cell infiltration by suppressing Th17 cell infiltration and IL-17 signal transduction in breast cancer.

研究背景：近年来，白细胞介素17（IL-17）细胞因子家族与乳腺癌的关联已得到广泛研究。多项研究证实，在雌激素受体（ER）阴性或三阴性乳腺癌组织中，细胞因子IL-17A的表达水平显著升高。在雌激素受体低表达的乳腺癌中，IL-17A信号通路的上调与程序性细胞死亡蛋白1（PD-1）及程序性死亡配体1（PD-L1）的表达增加相关，还可能促进肿瘤组织内CD8+T细胞的浸润。本研究旨在明确雌激素受体是否可通过减少辅助性T细胞17（Th17）浸润、抑制IL-17信号通路，进而下调PD-1/PD-L1的表达、降低CD8+T细胞浸润，最终影响乳腺癌的免疫微环境。
研究方法：本研究基于癌症基因组图谱乳腺癌数据集，根据雌激素受体状态与PAM50固有亚型对样本进行分组，对比各组间IL-17家族细胞因子及Th17细胞特征性细胞因子的表达差异；筛选出随雌激素受体水平变化呈现差异表达的IL-17信号通路相关基因；对比不同雌激素受体状态、不同IL-17A/IL-17F表达水平的乳腺癌样本中PD-1与PD-L1的表达水平；开展PD-1/PD-L1表达与IL-17信号通路相关基因表达的相关性分析；探究IL-17信号通路相关基因的表达与乳腺癌免疫微环境的关联。
研究结果：高雌激素受体水平可下调IL-17A、IL-17C及IL-17F的表达，而上调作为IL-17信号通路抑制剂的IL-17E（IL25）的表达。在ER阴性乳腺癌中，Th17细胞特征性细胞因子的表达水平显著升高。在雌激素受体高表达的乳腺癌组织中，IL-17A/IL-17F信号通路下游产物编码基因的表达呈下调趋势。PD-1/PD-L1的表达上调与乳腺癌的ER阴性状态、IL-17A阳性状态、IL-17F阳性状态及IL-17信号通路相关基因上调显著相关。IL-17信号转导的增强与CD8+T细胞浸润增加及乳腺癌免疫微环境改变密切相关。
研究结论：在乳腺癌中，高雌激素受体水平可通过抑制辅助性T细胞17浸润与IL-17信号转导，下调PD-1/PD-L1的表达并减少CD8+T细胞浸润。