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.
Highlights
Major histocompatibility complex (MHC) genes in humans are referred to as human leukocyte antigen (HLA) genes
We show in this paper, the association between down–regulation in expression of IGF-1 and enhancement in the cell surface expression of HLA class 1 molecules in human Glioblastoma cells and Glioblastoma cell lines
This led to the hypothesis that decrease in intracellular IGF-1 would enhance components of the endogenous antigen processing and presentation pathway
Summary
Major histocompatibility complex (MHC) genes in humans are referred to as human leukocyte antigen (HLA) genes. The HLA class 1 peptide complex is transported to the cell surface to be presented to cytotoxic T lymphocytes (CTL). This antigenprocessing machinery and HLA-1 restricted antigen-presentation pathway is believed to have a role in the activation of CTL mediated immunogenicity [9]. This machinery and the MHC-1 restricted antigen presentation pathway are downregulated in many different cancer tissues and cancer cell lines [10,11,12,13,14]. This has led to the hypothesis that the defective pathway may have a significant role in loss of immuno-surveillance and possibly in causation of cancer
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