title: Tumor antigen processing and presentation depend critically on dendritic cell type and the mode of antigen delivery.
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.
authors.affiliation: Ludwig Institute for Cancer Research, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Max
authors.initials: M
authors.lastname: Schnurr
authors.forename: Qiyuan
authors.initials: Q
authors.lastname: Chen
authors.forename: Amanda
authors.initials: A
authors.lastname: Shin
authors.forename: Weisan
authors.initials: W
authors.lastname: Chen
authors.forename: Tracey
authors.initials: T
authors.lastname: Toy
authors.forename: Corinna
authors.initials: C
authors.lastname: Jenderek
authors.forename: Simon
authors.initials: S
authors.lastname: Green
authors.forename: Lena
authors.initials: L
authors.lastname: Miloradovic
authors.forename: Debbie
authors.initials: D
authors.lastname: Drane
authors.forename: Ian D
authors.initials: ID
authors.lastname: Davis
authors.forename: Jose
authors.initials: J
authors.lastname: Villadangos
authors.forename: Ken
authors.initials: K
authors.lastname: Shortman
authors.forename: Eugene
authors.initials: E
authors.lastname: Maraskovsky
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cebon
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology*; D000936:Antigen-Antibody Complex / Q000276:immunology; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D002478:Cells, Cultured; D002784:Cholesterol / Q000008:administration & dosage / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D004338:Drug Combinations; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008565:Membrane Proteins / Q000008:administration & dosage / Q000276:immunology*; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D010743:Phospholipids / Q000008:administration & dosage / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000276:immunology; D012503:Saponins / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000936:Antigen-Antibody Complex; D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D004338:Drug Combinations; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C493786:ISCOMATRIX; D008565:Membrane Proteins; D010743:Phospholipids; D012503:Saponins; D002784:Cholesterol; D046988:Proteasome Endopeptidase Complex