HE4 suppresses the expression of osteopontin in mononuclear cells and compromises their cytotoxicity against ovarian cancer cells

Clin Exp Immunol. 2018 Sep;193(3):327-340. doi: 10.1111/cei.13153.

Abstract

Ovarian cancers are known to evade immunosurveillance and to orchestrate a suppressive immune microenvironment. Here we examine the role of human epididymis protein 4 (HE4), an ovarian cancer biomarker, in immune evasion. Through modified subtractive hybridization analyses we have characterized the gene targets of HE4 in human peripheral blood mononuclear cells (PBMCs), and established a preliminary mechanism for HE4-mediated immune failure in ovarian tumours. Upon exposure of purified PMBCs to HE4, osteopontin (OPN) and dual-specificity phosphatase 6 (DUSP6) emerged as the most suppressed and up-regulated genes, respectively. SKOV3 and OVCAR8, human ovarian carcinoma cell lines, exhibited enhanced proliferation in conditioned media from HE4-exposed PBMCs, an effect that was attenuated by the addition of recombinant OPN or OPN-inducible cytokines [interleukin (IL)-12 and interferon (IFN)-Ɣ]. Additionally, upon co-culture with PBMCs, HE4-silenced SKOV3 cells were found to be more susceptible to cytotoxic cell death. The relationship between HE4 and OPN was reinforced further through the analysis of serous ovarian cancer patient samples. In these biopsy specimens, the number of OPN+ T cells correlated positively with progression free survival (PFS) and inversely with serum HE4 level. Taken together, these findings show that HE4 enhances ovarian cancer tumorigenesis by compromising OPN-mediated T cell activation.

Keywords: T cells; cancer; cytokines.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation
  • Cytotoxicity, Immunologic
  • Dual Specificity Phosphatase 6 / genetics
  • Dual Specificity Phosphatase 6 / metabolism*
  • Female
  • Gene Expression Regulation
  • Humans
  • Immune Tolerance
  • Interferon-gamma / metabolism
  • Interleukin-12 / metabolism
  • Leukocytes, Mononuclear / physiology*
  • Osteopontin / genetics
  • Osteopontin / metabolism*
  • Ovarian Neoplasms / immunology*
  • Ovarian Neoplasms / mortality
  • Proteins / genetics
  • Proteins / metabolism*
  • RNA, Small Interfering / genetics
  • Survival Analysis
  • T-Lymphocytes / immunology*
  • Tumor Escape
  • Tumor Microenvironment
  • WAP Four-Disulfide Core Domain Protein 2

Substances

  • Proteins
  • RNA, Small Interfering
  • WAP Four-Disulfide Core Domain Protein 2
  • WFDC2 protein, human
  • Osteopontin
  • Interleukin-12
  • Interferon-gamma
  • DUSP6 protein, human
  • Dual Specificity Phosphatase 6