title: WHO grade associated downregulation of MHC class I antigen-processing machinery components in human astrocytomas: does it reflect a potential immune escape mechanism?
abstract: Defects of major histocompatibility complex (MHC) class I antigen-processing machinery (APM) components have been shown to contribute to immune escape of malignant cells. We investigated the expression of APM components in astrocytomas without detectable defects in HLA class I antigen expression and correlated it with grade of malignancy. Quantitative immunohistochemical analysis of astrocytomas revealed reduced expression of the cytosolic proteasome subunit low molecular weight protein 2 (LMP2), the endoplasmatic reticulum (ER) transporter associated with antigen processing-1 (TAP1), and the ER chaperone beta2-microglobulin (beta2m) in astrocytoma cells when compared to astrocytes from nonpathological brain. Among human WHO grade II-IV astrocytomas, downregulation of LMP2, TAP1 and beta2m correlated with grade of malignancy. Furthermore, astrocytoma cell lines (n = 12) expressed all APM components analyzed at levels comparable to dendritic cells (DC), which were used for comparative purposes. However, upregulation of beta2m after stimulation with inflammatory cytokines was significantly lower in astrocytoma cell lines than in control cells. Our results support the hypothesis that coordinated downregulation or impaired upregulation of certain HLA class I APM components may serve as a mechanism for astrocytoma cells to evade the host's immune response, even if HLA class I antigen surface expression is not altered.
authors.affiliation: Department of General Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mehling
authors.forename: Perikles
authors.initials: P
authors.lastname: Simon
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Richard
authors.initials: R
authors.lastname: Meyermann
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017951:Antigen Presentation / Q000276:immunology*; D001254:Astrocytoma / Q000276:immunology* / Q000473:pathology; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D003546:Cysteine Endopeptidases / Q000096:biosynthesis; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D019139:Tumor Escape / Q000276:immunology*; D014944:World Health Organization; D001613:beta 2-Microglobulin / Q000096:biosynthesis
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; C073119:TAP1 protein, human; D001613:beta 2-Microglobulin; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases