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Blood, 15 March 2005, Vol. 105, No. 6, pp. 2465-2472.
Prepublished online as a Blood First Edition Paper on November 16, 2004; DOI 10.1182/blood-2004-08-3105.
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Submitted August 16, 2004
Accepted November 10, 2004
Tumor antigen processing and presentation depends critically on dendritic cell type and the mode of antigen delivery
Max Schnurr, Qiyuan Chen, Amanda Shin, Weisan Chen, Tracey Toy, Corinna Jenderek, Simon Green, Lena Miloradovic, Debbie Drane, Ian D Davis, Jose Villadangos, Ken Shortman, Eugene Maraskovsky*, and Jonathan Cebon
Austin Health, Ludwig Institute for Cancer Research, Heidelberg, VIC, Australia
CSL limited, Parkville, VIC, Australia
Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
Austin Health, Ludwig Institute for Cancer Research, Heidelberg, VIC, Australia; CSL limited, Parkville, VIC, Australia
* Corresponding author; email: eugene_maraskovsky{at}csl.com.au.
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 three 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 MHC 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 ISCOMATRIXTM 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 DC. IC targeted a slow, proteasome-dependent cross-presentation pathway, whereas 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.
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