title: Elevation of c-MYC disrupts HLA class II-mediated immune recognition of human B cell tumors.
abstract: Elevated levels of the transcription factor c-myc are strongly associated with various cancers, and in particular B cell lymphomas. Although many of c-MYC's functions have been elucidated, its effect on the presentation of Ag through the HLA class II pathway has not been reported previously. This is an issue of considerable importance, given the low immunogenicity of many c-MYC-positive tumors. We report in this paper that increased c-MYC expression has a negative effect on the ability of B cell lymphomas to functionally present Ags/peptides to CD4(+) T cells. This defect was associated with alterations in the expression of distinct cofactors as well as interactions of antigenic peptides with class II molecules required for the presentation of class II-peptide complexes and T cell engagement. Using early passage Burkitt's lymphoma (BL) tumors and transformed cells, we show that compared with B lymphoblasts, BL cells express decreased levels of the class II editor HLA-DM, lysosomal thiol-reductase GILT, and a 47-kDa enolase-like protein. Functional Ag presentation was partially restored in BL cells treated with a c-MYC inhibitor, demonstrating the impact of this oncogene on Ag recognition. This restoration of HLA class II-mediated Ag presentation in early passage BL tumors/cells was linked to enhanced HLA-DM expression and a concurrent decrease in HLA-DO in BL cells. Taken together, these results reveal c-MYC exerts suppressive effects at several critical checkpoints in Ag presentation, which contribute to the immunoevasive properties of BL tumors.
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center and Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Jason M
authors.initials: JM
authors.lastname: God
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center and Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Christine
authors.initials: C
authors.lastname: Cameron
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center and Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Janette
authors.initials: J
authors.lastname: Figueroa
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center and Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Shereen
authors.initials: S
authors.lastname: Amria
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center and Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Azim
authors.initials: A
authors.lastname: Hossain
authors.affiliation: Department of Gene Vectors, German Research Center for Environmental Health, 81377 Munich, Germany;
authors.forename: Bettina
authors.initials: B
authors.lastname: Kempkes
authors.affiliation: Institute of Clinical Molecular Biology and Tumor Genetics, German Research Center for Environmental Health, 81377 Munich, Germany;
authors.forename: Georg W
authors.initials: GW
authors.lastname: Bornkamm
authors.affiliation: Department of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Stuart
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202.
authors.forename: Janice S
authors.initials: JS
authors.lastname: Blum
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center and Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425; haque@musc.edu.
authors.forename: Azizul
authors.initials: A
authors.lastname: Haque
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D015153:Blotting, Western; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000276:immunology*; D013058:Mass Spectrometry; D016271:Proto-Oncogene Proteins c-myc / Q000276:immunology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D000949:Histocompatibility Antigens Class II; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc