title: Posttranscriptional Control of PD-L1 Expression by 17β-Estradiol via PI3K/Akt Signaling Pathway in ERα-Positive Cancer Cell Lines.
abstract: Estrogen is a well-known oncogenic driver in endometrial (ECs) and breast cancers (BCs). Programmed cell death protein 1 (PD-1) and its ligands PD-1 Ligand 1 (PD-L1) and PD-L2 have been shown to mediate immune evasion of the tumor cells. The purpose of the present study was to assess the effects of estrogen on PD-L1 and PD-L2 expression in EC and BC cell lines.
  
  
  
  17β-Estradiol (E2)-induced expression of PD-L1 and PD-L2 and possible signaling pathway were investigated in EC and BC cells. Coculture of T cells and cancer cells with E2 stimulation was performed to assess the functions of T cells.
  
  
  
  We found that E2 increased expression of PD-L1, but not PD-L2, protein via activation of phosphoinositide 3-kinase (PI3K)/Akt pathway in Ishikawa and Michigan Cancer Foundation-7 (MCF-7) cells. Phosphoinositide 3-kinase and Akt inhibitors could block E2's effects. 17β-Estradiol did not increase PD-L1 mRNA transcription, but stabilized PD-L1 mRNA. 17β-Estradiol's effects were only observed in estrogen receptor α (ERα)-positive Ishikawa and MCF-7 cells, but not in ERα-negative MDA-MB-231 cells. Coculture of Ishikawa or MCF-7 cells with T cells inhibited expression of interferon-γ and interleukin-2 and increased BCL-2-interacting mediator of cell death expression in the presence of E2.
  
  
  
  This study provides the first evidence that estrogen upregulates PD-L1 protein expression in ERα-positive EC and BC cells to suppress immune functions of T cells in the tumor microenvironment, demonstrating a new mechanism of how estrogen drives cancer progression.
authors.affiliation: *Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA; †Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu; ‡Department of Clinical Medicine, the First Affiliated Hospital, Shanxi University of Chinese Medicine, Xianyang; §Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu; and ∥Department of Gastroenterology, Wuchang Hospital, Wuhan, China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Yang
authors.forename: Feng
authors.initials: F
authors.lastname: Huang
authors.forename: Jiandong
authors.initials: J
authors.lastname: Mei
authors.forename: Xun
authors.initials: X
authors.lastname: Wang
authors.forename: Qiuyang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Hongjing
authors.initials: H
authors.lastname: Wang
authors.forename: Mingrong
authors.initials: M
authors.lastname: Xi
authors.forename: Zongbing
authors.initials: Z
authors.lastname: You
mesh_terms: D060890:B7-H1 Antigen / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D061986:MCF-7 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D060890:B7-H1 Antigen; D004958:Estradiol; D047628:Estrogen Receptor alpha; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; C423236:CD274 protein, human; C506487:ESR1 protein, human