Abstract
Escape from immune recognition has been hypothesized to be a factor in carcinogenesis. It may be mediated for many cancers through down-regulation in the MHC class 1 antigen processing and presentation pathway. TAP-1, TAP-2, tightly linked to LMP-2 and LMP-7 are multiple components of the endogenous, antigen presentation pathway machinery. We addressed the question of alterations in this pathway in human Glioblastoma (HGB) and of its relationship to modulation in expression of IGF-1 that is highly expressed in this cancer. Deficiencies in expression of TAP-1 were demonstrated by RT-PCR and/or by immuno-flow cytometry in the HGB cell line T98G obtained from ATCC, and in 3 of 4 human cell lines established from patients with Glioblastoma Multiforme. Deficiencies in expression of TAP-2 were observed in 3 of 4, deficiencies in expression of LMP-2 in 4 of 4 and deficiencies in LMP-7 in 3 of 4 HGB cell lines examined by RT-PCR and Western blot. Following down-regulation of IGF-1 by transfection with the pAnti IGF-1 vector that expresses IGF-1 RNA in antisense orientation, or by the exogenous addition of IGF-1 receptor monoclonal antibody to cell culture media, the deficiencies in components of the MHC-1 antigen presentation pathway were up-regulated and/or rescued in all HGB cell lines tested. Moreover, this up-regulation in expression was aborted by addition of 100 ng/ml of IGF-1 to the culture media. Unlike in the case of IFN-γ, the restoration of TAP-1 and LMP-2 by down-regulation of IGF-1 in Glioblastoma cells was not correlated to the tyrosine phosphorylation of STAT 1. In summary, the simultaneous reversion in expression of the multiple constituents of MHC-1 antigen processing path and up-regulation in expression of MHC-1 occurring with down-regulation in IGF-1 may have a role in reinforcement of immunity against tumor antigen(s) in some animal cancers and in humans with Glioblastoma Multiforme.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 2
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ATP Binding Cassette Transporter, Subfamily B, Member 3
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism
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Antigen Presentation / genetics*
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Antigens, Neoplasm / metabolism
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B7-1 Antigen / metabolism
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Cell Line, Tumor
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Cysteine Endopeptidases / genetics
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Cysteine Endopeptidases / metabolism
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Down-Regulation
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Glioblastoma / genetics*
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Glioblastoma / immunology*
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Glioblastoma / metabolism
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Histocompatibility Antigens Class I / metabolism*
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Humans
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Insulin-Like Growth Factor I / antagonists & inhibitors
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Insulin-Like Growth Factor I / genetics*
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Neoplasm / genetics
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RNA, Neoplasm / metabolism
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 2
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ATP Binding Cassette Transporter, Subfamily B, Member 3
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ATP-Binding Cassette Transporters
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Antigens, Neoplasm
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B7-1 Antigen
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Histocompatibility Antigens Class I
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RNA, Messenger
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RNA, Neoplasm
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TAP1 protein, human
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LMP-2 protein
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TAP2 protein, human
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Insulin-Like Growth Factor I
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Cysteine Endopeptidases
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LMP7 protein
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Proteasome Endopeptidase Complex
Grants and funding
The work was supported by American Cancer Society grant CN-8 A, a grant from the Ohio Board of Regents and by gifts from the following benefactors: Marcia & Robert Williams, Regina & David Letterman, the Paul Newman Foundation, Mrs. Helen Wright, Mr. & Mrs. Edward Yoman, Mrs. Elizabeth Becker, Kimberly Birn & family, Mrs. Verna Warpula, Herbert Braverman, John D. Proctor, Harold & Clare Minoff, James & Rosemary Koehler, Wm. Gustaferro & family, Edward & Mary Lasko, and other unnamed donors. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.