Tumor escape from immune recognition: Loss of HLA-A2 melanoma cell surface expression is associated with a complex rearrangement of the short arm of chromosome 6

Markus J. Maeurer, Susanne M. Gollin, Walter J. Storkus, William Swaney, Julia Karbach, Dina Martin, Chiara Castelli, Russell Salter, Alex Knuth, Michael T. Lotze

Research output: Contribution to journalArticle

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Abstract

Specific CD8+ CTL recognition of melanoma requires expression of MHC class I molecules as well as melanoma-associated peptide epitopes. Human melanoma cells may escape immune recognition by a variety of means, including global or allelic down-regulation of MHC class I molecules. Stable MHC class I cell surface expression requires delivery of cytosolic peptides into the endoplasmic reticulum by the peptide transporter molecules TAP1 and TAP2, with peptides subsequently transported to the cell surface in complexes containing MHC class I heavy chain and β2-microglobulin. We have evaluated a series of mechanisms resulting in MHC class I down-regulation in a human melanoma cell line, Mz18, typed as HLA-A2+, A3+, B7+, B57+ Cw1+, and Cw6+ by genomic PCR analysis. The melanoma cell line Mz18 exhibits a global down-regulation of MHC class I heavy chain transcripts; β2-microglobulin; the proteasome subunits LMP2/7, involved in generating cytosolic peptide fragments; and the peptide transporter molecules TAP1 and TAP2, involved in peptide transport from the cytosol into the endoplasmic reticulum. IFN-γ treatment of Mz18 melanoma cells leads to up-regulation of LMP2/7 and TAP1/2, as well as to up-regulation of HLA-B and HLA-C MHC loci alleles, but not HLA-A2 or HLA-A3. Karyotypic analysis and fluorescence in situ hybridization with chromosome 6 and MHC class I-specific probes showed complex rearrangement of one chromosome 6 involving the MHC class I locus on 6p and translocation of 6q to the long arm of chromosome 19. To evaluate the capability of melanoma Mz18 to present tumor-specific peptides to HLA-A2-restricted, melanoma-specific CTLs, we restored HLA-A2 surface expression by retroviral-mediated transfer of functional HLA-A2 cDNA. Melanoma peptides could only be presented and recognized by CTLs if the HLA-A2-transfected Mz18 cell line was first treated with IFN-γ, thereby restoring LMP2/7 and TAP1/2 expression and function. Because several melanoma antigens recognized by T cells have been reported to be presented by HLA-A2 (MART-1/Melan-A, tyrosinase, gp100, and MAGE-3), the loss of HLA-A2 molecules may represent an important mechanism by which many melanomas evade immune recognition. These findings suggest that patients entering clinical trials for immunotherapy with melanoma vaccines should be carefully examined for tumor cell allelic MHC class I loss and whether such MHC class I antigen down-regulation can be restored by cytokines.

Original languageEnglish
Pages (from-to)641-652
Number of pages12
JournalClinical Cancer Research
Volume2
Issue number4
Publication statusPublished - Apr 1996

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Tumor Escape
HLA-A2 Antigen
Chromosomes, Human, Pair 6
Melanoma
Peptides
Down-Regulation
HLA-A3 Antigen
Cell Line
Endoplasmic Reticulum
Up-Regulation
MART-1 Antigen
HLA-C Antigens
Melanoma-Specific Antigens
Chromosomes, Human, Pair 19
Histocompatibility Antigens Class I
Peptide Fragments
HLA-B Antigens
Monophenol Monooxygenase
Fluorescence In Situ Hybridization
Cytosol

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Maeurer, M. J., Gollin, S. M., Storkus, W. J., Swaney, W., Karbach, J., Martin, D., ... Lotze, M. T. (1996). Tumor escape from immune recognition: Loss of HLA-A2 melanoma cell surface expression is associated with a complex rearrangement of the short arm of chromosome 6. Clinical Cancer Research, 2(4), 641-652.

Tumor escape from immune recognition : Loss of HLA-A2 melanoma cell surface expression is associated with a complex rearrangement of the short arm of chromosome 6. / Maeurer, Markus J.; Gollin, Susanne M.; Storkus, Walter J.; Swaney, William; Karbach, Julia; Martin, Dina; Castelli, Chiara; Salter, Russell; Knuth, Alex; Lotze, Michael T.

In: Clinical Cancer Research, Vol. 2, No. 4, 04.1996, p. 641-652.

Research output: Contribution to journalArticle

Maeurer, MJ, Gollin, SM, Storkus, WJ, Swaney, W, Karbach, J, Martin, D, Castelli, C, Salter, R, Knuth, A & Lotze, MT 1996, 'Tumor escape from immune recognition: Loss of HLA-A2 melanoma cell surface expression is associated with a complex rearrangement of the short arm of chromosome 6', Clinical Cancer Research, vol. 2, no. 4, pp. 641-652.
Maeurer, Markus J. ; Gollin, Susanne M. ; Storkus, Walter J. ; Swaney, William ; Karbach, Julia ; Martin, Dina ; Castelli, Chiara ; Salter, Russell ; Knuth, Alex ; Lotze, Michael T. / Tumor escape from immune recognition : Loss of HLA-A2 melanoma cell surface expression is associated with a complex rearrangement of the short arm of chromosome 6. In: Clinical Cancer Research. 1996 ; Vol. 2, No. 4. pp. 641-652.
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