Rescue of MHC-1 Antigen Processing Machinery by Down-Regulation in Expression of IGF-1 in Human Glioblastoma Cells

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.

p53 overexpression increases chemosensitivity in multidrug-resistant osteosarcoma cell lines

“…IGF signaling is regulated by many factors, which are typically altered in cancer and has been proven to lead to MDR [14,24]. For example, glioblastoma cells highly express IGF-1 [25]. Breast cancer can increase IGF ligand expression (IGF-2, IGF-2), which is related to malignant resistance and transformation [26].…”

Epistemológica experiencia en la elaboración de tecnología biomolecular para estrategia de la inmunoterapia génica - Epistemological experience in the development of biomolecular technology for gene immunotherapy strategy

“…Para que la célula CD8+ ejerza su efecto citotóxico, es necesaria la formación de un puente entre esta y los antígenos de clase I del complejo mayor de histocompatibilidad (MHC I se relaciona con la expresión de TAP1 y TAP2) (Pan et al, 2013). En el bazo, los linfocitos citotóxicos son vehículizados a través de la sangre y se concentran en el tumor durante su regresión (Trojan et al, 1993(Trojan et al, , 1994Wongajornsilp et al, 2001).…”

“…Los CTL activados producen una respuesta inmune antitumoral. Abreviaturas: TAP 1,2 (transporter associated with antigen processing antigen); TK (tyrosine kinase); PI3K (phosphatidyinositol 3 kinase); PDK1 (phosphoinositide-dependent kinase 1); AKT (PKB, protein kinase B); Bcl 2 (key molecule of apoptose); GSK3 (glycogene synthetase kinase 3); GS (glycogene synthetasePKC (protein kinase C) Beckner et al (2005); Lemoine et al (2009);Chappert et al (2010); Pan et al (2013).…”

Natural Killer Cells Differentiate Human Adipose-Derived Stem Cells and Modulate Their Adipogenic Potential

“…Virally infected and malignant cell populations frequently have altered or diminished expression of major histocompatibility complex class I, which underlies a key mechanism by which natural killer cells are able to recognize and destroy these cells in their role within the innate immune system. 19,20 Interestingly, natural killer cell supernatant-treated cells also reliably showed increased expression of the differentiation marker B7H1, a cell surface marker that has been implicated in the immune evasion of certain tumors. 21 Recent studies on B7H1 suggest that expression of this cell surface marker may reflect the malignancy grade of certain human gliomas.…”