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Posttranscriptional Control of PD-L1 Expression by 17β-Estradiol via PI3K/Akt Signaling Pathway in ERα-Positive Cancer Cell Lines
  1. Lingyun Yang, MD,
  2. Feng Huang, MD, PhD,
  3. Jiandong Mei, MD, PhD,
  4. Xun Wang, MD, PhD,
  5. Qiuyang Zhang, PhD,
  6. Hongjing Wang, MD, PhD,
  7. Mingrong Xi, MD, PhD and
  8. Zongbing You, MD, PhD
  1. * Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA;
  2. Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu;
  3. Department of Clinical Medicine, the First Affiliated Hospital, Shanxi University of Chinese Medicine, Xianyang;
  4. § Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu; and
  5. Department of Gastroenterology, Wuchang Hospital, Wuhan, China.
  1. Address correspondence and reprint requests to Zongbing You, MD, PhD, Department of Structural and Cellular Biology, Tulane University, 1430 Tulane Ave, New Orleans, LA 70112. E-mail: zyou{at}tulane.edu; Mingrong Xi, MD, PhD, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, No. 20 Section 3 of South Renmin Road, Chengdu 610041, China. E-mail: xmrjzz{at}126.com.

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.

  • Estrogen
  • PD-1 Ligand 1 (PD-L1)
  • Phosphoinositide 3-kinase
  • Akt
  • Endometrial cancer
  • Breast cancer

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Footnotes

  • The authors declare no conflicts of interest.

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