Tumor antigen processing and presentation depend critically on dendritic cell type and the mode of antigen delivery.
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.
Schnurr
Max
M
Ludwig Institute for Cancer Research, Austin Health, Heidelberg, Victoria, Australia.
Chen
Qiyuan
Q
Shin
Amanda
A
Chen
Weisan
W
Toy
Tracey
T
Jenderek
Corinna
C
Green
Simon
S
Miloradovic
Lena
L
Drane
Debbie
D
Davis
Ian D
ID
Villadangos
Jose
J
Shortman
Ken
K
Maraskovsky
Eugene
E
Cebon
Jonathan
J
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
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