title: Multiple defects of the antigen-processing machinery components in human neuroblastoma: immunotherapeutic implications.
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 beta2 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-gamma 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-gamma, although enhancing neuroblastoma cell recognition by cytotoxic T cells, dampens their susceptibility to NK cells.
authors.affiliation: Laboratory of Oncology, G Gaslini Institute, Largo G Gaslini, Genova, Italy. lizziaraffaghello@ospedale-gaslini.ge.it
authors.forename: Lizzia
authors.initials: L
authors.lastname: Raffaghello
authors.forename: Ignazia
authors.initials: I
authors.lastname: Prigione
authors.forename: Paola
authors.initials: P
authors.lastname: Bocca
authors.forename: Fabio
authors.initials: F
authors.lastname: Morandi
authors.forename: Marta
authors.initials: M
authors.lastname: Camoriano
authors.forename: Claudio
authors.initials: C
authors.lastname: Gambini
authors.forename: Xinhui
authors.initials: X
authors.lastname: Wang
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.forename: Vito
authors.initials: V
authors.lastname: Pistoia
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation; D005260:Female; D005805:Genes, MHC Class I; D006680:HLA Antigens / Q000096:biosynthesis*; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000096:biosynthesis*; D008297:Male; D009447:Neuroblastoma / Q000276:immunology* / Q000473:pathology; D017154:Stromal Cells; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; D006680:HLA Antigens; D007371:Interferon-gamma