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Title: Tumor antigen processing and presentation depend critically on dendritic cell type and the mode of antigen delivery.
Authors: Schnurr, Max;Chen, Qiyuan;Shin, Amanda;Chen, Weisan;Toy, Tracey;Jenderek, Corinna;Green, Simon;Miloradovic, Lena;Drane, Debbie;Davis, Ian D;Villadangos, Jose;Shortman, Ken;Maraskovsky, Eugene;Cebon, Jonathan S
Affiliation: Ludwig Institute for Cancer Research, Austin Health, Heidelberg, Victoria, Australia.
Issue Date: 16-Nov-2004
Citation: Blood 2004; 105(6): 2465-72
Abstract: Dendritic cells (DCs) are being evaluated for cancer immunotherapy due to their unique ability to induce tumor-directed T-cell responses. Here we report that the type of human DC, the mode of activation, and the strategy for delivery of antigen are 3 critical factors for efficient stimulation of tumor-specific CD8+ and CD4+ T cells. Only CD1c+ blood DCs and monocyte-derived DCs (MoDCs) were capable of presenting epitopes of the full-length tumor antigen NY-ESO-1 on both major histocompatibility complex (MHC) class I (cross-presentation) and MHC II, whereas plasmacytoid DCs were limited to MHC II presentation. Cross-presentation was inefficient for soluble protein, but highly efficient for antigen-antibody immune complexes (NY-ESO-1/IC) and for protein formulated with ISCOMATRIX adjuvant (NY-ESO-1/IMX). DC activation with CD40L further enhanced cross-presentation efficiency. The mode of antigen delivery was found to be a determining factor for cytosolic proteolysis by DCs. Immune complexes (ICs) targeted a slow, proteasome-dependent cross-presentation pathway, whereas ISCOMATRIX (IMX) targeted a fast, proteasome-independent pathway. Both cross-presentation pathways resulted in a long-lived, T-cell stimulatory capacity, which was maintained for several days longer than for DCs pulsed with peptide. This may provide DCs with ample opportunities for sensitizing tumor-specific T cells against a broad array of tumor antigen epitopes in lymph nodes.
Internal ID Number: 15546948
DOI: 10.1182/blood-2004-08-3105
Type: Journal Article
Subjects: Adjuvants, Immunologic.administration & dosage
Antigen Presentation.drug effects.immunology
Antigen-Antibody Complex.immunology
Antigens, Neoplasm.administration & dosage.immunology
CD4-Positive T-Lymphocytes.immunology.pathology
CD8-Positive T-Lymphocytes.immunology.pathology
Cancer Vaccines.administration & dosage.immunology
Cells, Cultured
Cholesterol.administration & dosage.immunology
Dendritic Cells.immunology.pathology
Drug Combinations
Epitopes, T-Lymphocyte.immunology
Histocompatibility Antigens Class I.immunology
Histocompatibility Antigens Class II.immunology
Lymph Nodes.immunology.pathology
Membrane Proteins.administration & dosage.immunology
Phospholipids.administration & dosage.immunology
Plasma Cells.immunology.pathology
Proteasome Endopeptidase Complex.immunology
Saponins.administration & dosage.immunology
Appears in Collections:Journal articles

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