HLA-E protects glioma cells from NKG2D-mediated immune responses in vitro: implications for immune escape in vivo

J Neuropathol Exp Neurol. 2005 Jun;64(6):523-8. doi: 10.1093/jnen/64.6.523.

Abstract

The nonclassical MHC class I molecule HLA-E is the only known ligand for CD94/NKG2A and CD94/NKG2C expressed on NK and CD8+ alphabeta and gammadelta T cells. HLA-E may transmit either activating signals via CD94/NKG2C or inhibitory signals mediated by CD94/NKG2A. Here we show that HLA-E is expressed at mRNA and protein level in human long-term glioma cell lines, primary ex vivo polyclonal glioblastoma cell cultures and surgical glioblastoma specimens. Furthermore, immunohistochemistry revealed an enhanced in vivo expression of HLA-E in gliomas of lower grades and a massive overexpression in grade IV glioblastomas compared with normal CNS tissue. An immune-inhibitory effect of HLA-E on tumor-specific CTL has already been described. We show that siRNA-mediated silencing of HLA-E or blocking of CD94/NKG2A enables NKG2D-mediated lysis of 51Cr-labeled tumor cells by NK cells. Thus, our study provides the first evidence that expression and interaction of HLA-E on cancer cells with CD94/NKG2A expressed on lymphocytes compromises innate anti-tumor immune responses.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / pharmacology
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic / drug effects
  • Cytotoxicity, Immunologic / physiology
  • Flow Cytometry / methods
  • Gene Expression Regulation, Neoplastic / physiology*
  • Glioma / immunology*
  • Glioma / metabolism*
  • HLA Antigens / genetics
  • HLA Antigens / metabolism*
  • HLA-E Antigens
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Immunohistochemistry / methods
  • Killer Cells, Natural / metabolism
  • NK Cell Lectin-Like Receptor Subfamily C
  • NK Cell Lectin-Like Receptor Subfamily K
  • RNA, Small Interfering / pharmacology
  • Receptors, Immunologic / metabolism*
  • Receptors, Natural Killer Cell
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Signal Transduction / physiology
  • Transfection

Substances

  • Antigens, CD
  • HLA Antigens
  • Histocompatibility Antigens Class I
  • KLRC1 protein, human
  • KLRC2 protein, human
  • KLRK1 protein, human
  • NK Cell Lectin-Like Receptor Subfamily C
  • NK Cell Lectin-Like Receptor Subfamily K
  • RNA, Small Interfering
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell