title: Oxidized lipids block antigen cross-presentation by dendritic cells in cancer.
abstract: Cross-presentation is one of the main features of dendritic cells (DCs), which is critically important for the development of spontaneous and therapy-inducible antitumor immune responses. Patients, at early stages of cancer, have normal presence of DCs. However, the difficulties in the development of antitumor responses in patients with low tumor burden raised the question of the mechanisms of DC dysfunction. In this study, we found that, in differentiated DCs, tumor-derived factors blocked the cross-presentation of exogenous Ags without inhibiting the Ag presentation of endogenous protein or peptides. This effect was caused by intracellular accumulation of different types of oxidized neutral lipids: triglycerides, cholesterol esters, and fatty acids. In contrast, the accumulation of nonoxidized lipids did not affect cross-presentation. Oxidized lipids blocked cross-presentation by reducing the expression of peptide-MHC class I complexes on the cell surface. Thus, this study suggests the novel role of oxidized lipids in the regulation of cross-presentation.
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612;
authors.forename: Rupal
authors.initials: R
authors.lastname: Ramakrishnan
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Tyurin
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Tuyrin
authors.forename: Filippo
authors.initials: F
authors.lastname: Veglia
authors.forename: Thomas
authors.initials: T
authors.lastname: Condamine
authors.forename: Andrew
authors.initials: A
authors.lastname: Amoscato
authors.forename: Dariush
authors.initials: D
authors.lastname: Mohammadyani
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Johnson
authors.forename: Lan Min
authors.initials: LM
authors.lastname: Zhang
authors.forename: Judith
authors.initials: J
authors.lastname: Klein-Seetharaman
authors.forename: Esteban
authors.initials: E
authors.lastname: Celis
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.forename: Dmitry I
authors.initials: DI
authors.lastname: Gabrilovich
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D045142:Cross-Priming / Q000276:immunology*; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008055:Lipids / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010047:Ovalbumin / Q000276:immunology; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000276:immunology
chemical_list: D017077:Culture Media, Conditioned; D015853:Cysteine Proteinase Inhibitors; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D008055:Lipids; C110366:OVA-8; D010446:Peptide Fragments; C067713:lactacystin; D007371:Interferon-gamma; D010047:Ovalbumin; D000111:Acetylcysteine