Posttranscriptional Control of PD-L1 Expression by 17β-Estradiol via PI3K/Akt Signaling Pathway in ERα-Positive Cancer Cell Lines.

Abstract

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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: Lingyun Yang, Feng Huang, Jiandong Mei, Xun Wang, Qiuyang Zhang, Hongjing Wang, Mingrong Xi, Zongbing You
• Journal: International journal of gynecological cancer : official journal of the International Gynecological Cancer Society (Int J Gynecol Cancer) Vol. 27 Issue 2 Pg. 196-205 (02 2017) ISSN: 1525-1438 [Electronic] England
• PMID: 27870715 (Publication Type: Journal Article)

Chemical References

• B7-H1 Antigen
• CD274 protein, human
• ESR1 protein, human
• Estrogen Receptor alpha
• RNA, Messenger
• Estradiol
• Proto-Oncogene Proteins c-akt

Topics

• B7-H1 Antigen (biosynthesis, genetics)
• Breast Neoplasms (enzymology, genetics, immunology, metabolism)
• Cell Line, Tumor
• Endometrial Neoplasms (enzymology, genetics, immunology, metabolism)
• Estradiol (pharmacology)
• Estrogen Receptor alpha (biosynthesis)
• Female
• Humans
• Jurkat Cells
• MCF-7 Cells
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA Processing, Post-Transcriptional (drug effects)
• RNA, Messenger (genetics, metabolism)
• Signal Transduction (drug effects)
• T-Lymphocytes (drug effects, immunology)