Shuai Chong, Yang Xinmei, Pan Hongming, Han Weidong
Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Department of Oncology, The First Affiliated Hospital of Jiaxing University, Jiaxing, China.
Front Oncol. 2020 Sep 25;10:582863. doi: 10.3389/fonc.2020.582863. eCollection 2020.
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. 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. High levels of ER decreased the expression of IL-17A, IL-17C, and IL-17F but increased the expression of IL-17E (), 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. 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.
近年来，细胞因子白细胞介素17（IL-17）家族与乳腺癌之间的关系得到了广泛研究。许多研究表明，在雌激素受体（ER）阴性或三阴性乳腺癌中，细胞因子IL-17A水平升高。IL-17A信号上调与ER低表达乳腺癌中程序性细胞死亡蛋白1（PD-1）和程序性死亡配体1（PD-L1）表达增加相关，并可能提高肿瘤组织中CD8 T细胞的浸润。本研究旨在确定ER是否通过减少辅助性T细胞17（Th17）细胞浸润和抑制乳腺癌中的IL-17信号来下调PD-1/PD-L1的表达、减少CD8 T细胞浸润并影响免疫微环境。癌症基因组图谱乳腺癌数据集中的样本按ER状态和PAM50内在亚型分组。比较各组中IL-17家族细胞因子和Th17细胞特征性细胞因子的表达。鉴定根据ER水平差异表达的IL-17信号通路相关基因。比较不同ER状态和IL-17A/IL-17F表达水平的乳腺癌样本中PD-1和PD-L1水平。对PD-1/PD-L1表达与IL-17信号通路相关基因进行相关性分析。研究IL-17信号通路相关基因表达与免疫微环境的关联。高水平的ER降低了IL-17A、IL-17C和IL-17F的表达，但增加了IL-17E（）的表达，IL-17E作为IL-17信号的抑制剂。ER阴性乳腺癌中Th17细胞特征性细胞因子的表达水平显著增加。在ER高表达的乳腺癌中，编码IL-17A/IL-17F信号下游产物的基因表达水平下调。PD-1/PD-L1表达增加与乳腺癌中的ER阴性状态、IL-17A阳性状态、IL-17F阳性状态以及IL-17信号通路相关基因上调有关。增强的IL-17信号转导与乳腺癌中CD8 T细胞浸润增加和免疫微环境变化有关。高雌激素受体水平通过抑制乳腺癌中的Th17细胞浸润和IL-17信号转导来降低PD-1/PD-L1表达和CD8 T细胞浸润。
