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

Oncogene volume 24, pages 4634–4644 (2005)Cite this article

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.

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Acknowledgements

We thank Mr Federico Comanducci for the help in immunohistochemical studies, Dr Emil Bogenmann for the kind gift of the HTLA 230 cell line and Mrs Chiara Bernardini for the excellent secretarial assistance. We are deeply indebted to Dr Giorgio Parmiani for critical revision of the manuscript, criticism and suggestions. This work has been supported by grants from the Ministero della Salute (Ricerca Corrente and Ricerca Finalizzata), the Ministero dell'Università e della Ricerca, and the Compagnia di San Paolo to VP and by PHS Grant R01 CA 67108 awarded by the National Cancer Institute, DHHS to SF. LR was the recipient of a fellowship from Italian Ministry of University and Research.

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  1. Lizzia Raffaghello and Ignazia Prigione: These two authors contributed equally to this work

Authors and Affiliations

  1. Laboratory of Oncology, G Gaslini Institute, Largo G Gaslini, Genova, Italy

    Lizzia Raffaghello, Ignazia Prigione, Paola Bocca, Fabio Morandi, Marta Camoriano & Vito Pistoia

  2. Laboratory of Pathology, G Gaslini Institute, Genova, Italy

    Claudio Gambini

  3. Department of Immunology, Roswell Park Cancer Center, Buffalo, NY, USA

    Xinhui Wang & Soldano Ferrone

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  1. Lizzia Raffaghello
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Correspondence to Lizzia Raffaghello.

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Raffaghello, L., Prigione, I., Bocca, P. et al. Multiple defects of the antigen-processing machinery components in human neuroblastoma: immunotherapeutic implications. Oncogene 24, 4634–4644 (2005). https://doi.org/10.1038/sj.onc.1208594

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