Multiple defects of the antigen-processing machinery components in human neuroblastoma: Immunotherapeutic implications

Lizzia Raffaghello, Ignazia Prigione, Paola Bocca, Fabio Morandi, Marta Camoriano, Claudio Gambini, Xinhui Wang, Soldano Ferrone, Vito Pistoia

Research output: Contribution to journalArticlepeer-review

Abstract

Low expression of human leukocyte antigen (HLA) class I in human tumors may be related to defects of the antigen-processing machinery (APM) components. Neuroblastoma cells are virtually HLA class I negative, but (i) the underlying mechanisms are unknown, and (ii) expression of the APM components has never been investigated. Here we have used a panel of novel monoclonal antibodies to proteasomal and immunoproteasomal components, chaperons and transporter associated with antigen processing (TAP) to characterize 24 stroma-poor neuroblastoma tumors and six neuroblastoma cell lines. Primary tumors showed defects in the expression of zeta, tapasin, TAP1 or TAP2, HLA class I heavy chain and β2 microglobulin, LMP2 and LMP7, as compared to normal adrenal medulla. Neuroblastoma cell lines displayed roughly similar patterns of APM expression in comparison to primary tumors. Incubation of neuroblastoma cell lines with interferon-γ caused upregulation of HLA class I molecules and reduced lysis by killer inhibitory receptor HLA ligand-matched NK cells. Defects in APM components explain reduced peptide loading on HLA class I molecules, their instability and failure to be expressed on the cell surface. HLA class I upregulation by interferon-γ, although enhancing neuroblastoma cell recognition by cytotoxic T cells, dampens their susceptibility to NK cells.

Original languageEnglish
Pages (from-to)4634-4644
Number of pages11
JournalOncogene
Volume24
Issue number29
DOIs
Publication statusPublished - Jul 7 2005

Keywords

  • Antigen-processing machinery
  • Immune evasion
  • MHC downregulation
  • Pediatric tumor

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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