Downregulation and/or release of NKG2D ligands as immune evasion strategy of human neuroblastoma

Neoplasia. Sep-Oct 2004;6(5):558-68. doi: 10.1593/neo.04316.


Neuroblastoma (NB) is a pediatric extracranial tumor characterized by downregulation of human leukocyte antigen class I and defects of the antigen processing machinery, two features that make it an appropriate target for natural killer (NK)-mediated lysis. NKG2D is an activating immunoreceptor expressed by cytotoxic T lymphocytes and NK cells. The ligands for NKG2D are the major histocompatibility complex class I-related chain (MIC)A and MICB glycoproteins, and the UL-16-binding proteins (ULBPs). Here, the expression of NKG2D ligands was investigated in human primary NB tumors and cell lines because scanty information is available on this issue. MICA, MICB, and ULBP transcripts were found in most tumors and cell lines. MICA protein was detected in some NB cell lines but not in primary tumors. A soluble form of MICA (sMICA) was identified in most patient sera and in some cell line supernatants. sMICA downregulated surface NKG2D in normal peripheral blood CD8(+) cells and decreased NK-mediated killing of MICA(+) NB cells. MICB was detected exclusively in the cytosol of primary tumors and cell lines. Approximately 50% of primary tumors expressed ULBP-2, but not ULBP-1 or -3. ULBP-3 was expressed in 5 of 9 cell lines, ULBP-2 in 2 of 9, whereas ULBP-1 was never detected. These studies delineate novel potential pathways of tumor escape and immunodeficiency in NB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes / immunology
  • Carrier Proteins / analysis
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Down-Regulation / genetics*
  • GPI-Linked Proteins
  • Gene Expression
  • Histocompatibility Antigens Class I / analysis
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Membrane Proteins
  • NK Cell Lectin-Like Receptor Subfamily K
  • Neuroblastoma / genetics
  • Neuroblastoma / immunology*
  • Neuroblastoma / metabolism
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Receptors, Immunologic / metabolism*
  • Receptors, Natural Killer Cell
  • Tumor Escape* / genetics


  • Carrier Proteins
  • GPI-Linked Proteins
  • Histocompatibility Antigens Class I
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • KLRK1 protein, human
  • Ligands
  • MHC class I-related chain A
  • MICB antigen
  • Membrane Proteins
  • NK Cell Lectin-Like Receptor Subfamily K
  • RNA, Messenger
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell
  • ULBP1 protein, human
  • ULBP2 protein, human
  • ULBP3 protein, human