Table_3_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.
History
References
- https://doi.org//10.1097/JBR.0000000000000010
- https://doi.org//10.1097/JBR.0000000000000008
- https://doi.org//10.1016/j.critrevonc.2014.09.003
- https://doi.org//10.3892/mmr.2012.1036
- https://doi.org//10.1158/0008-5472.CAN-08-0206
- https://doi.org//10.1038/nature14282
- https://doi.org//10.1038/srep03456
- https://doi.org//10.1186/bcr2195
- https://doi.org//10.1111/his.12156
- https://doi.org//10.1007/s00432-017-2431-5
- https://doi.org//10.1038/nrc3239
- https://doi.org//10.1080/2162402X.2015.1085148
- https://doi.org//10.18632/oncotarget.3216
- https://doi.org//10.1186/s40064-016-2513-x
- https://doi.org//10.18632/oncotarget.13819
- https://doi.org//10.1186/bcr3148
- https://doi.org//10.1371/journal.pmed.1002194
- https://doi.org//10.1186/s13058-015-0632-x
- https://doi.org//10.1371/journal.pone.0095475
- https://doi.org//10.1038/s41587-020-0546-8
- https://doi.org//10.1158/0008-5472.CAN-17-0307
- https://doi.org//10.1186/s13059-016-1028-7
- https://doi.org//10.1016/j.cyto.2013.07.022
- https://doi.org//10.1016/j.cyto.2008.12.024
- https://doi.org//10.1084/jem.20061738
- https://doi.org//10.1155/2015/314620
- https://doi.org//10.1016/j.cyto.2014.09.011
- https://doi.org//10.1111/prd.12083
- https://doi.org//10.1084/jem.191.7.1233
- https://doi.org//10.1126/scisignal.2003699
- https://doi.org//10.1038/ni.2427
- https://doi.org//10.1371/journal.pone.0044552
- https://doi.org//10.1002/jcb.24165
- https://doi.org//10.1016/j.clim.2015.09.014
- https://doi.org//10.1007/s12013-011-9276-3
- https://doi.org//10.1111/cas.14174
- https://doi.org//10.1016/j.imlet.2017.02.006
- https://doi.org//10.1136/gutjnl-2015-310016
- https://doi.org//10.1186/bcr1648
- https://doi.org//10.1002/(SICI)1097-0215(19991022)84:5<533::AID-IJC16>3.0.CO;2-J
- https://doi.org//10.1126/scitranslmed.aad7118
- https://doi.org//10.1016/j.canlet.2008.03.018
- https://doi.org//10.12659/MSM.918281
- https://doi.org//10.1371/journal.pone.0221721
- https://doi.org//10.3390/ijms21103457