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* Department of Internal Medicine and
Division of Clinical Pharmacology, University of Munich, Munich, Germany;
Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences, Austin Health, Heidelberg, Victoria, Australia; and
CSL Limited, Parkville, Victoria, Australia
Cancer vaccines aim to induce antitumor CTL responses, which require cross-presentation of tumor Ag to CTLs by dendritic cells (DCs). Adjuvants that facilitate cross-presentation of vaccine Ag are therefore key for inducing antitumor immunity. We previously reported that human DCs could not efficiently cross-present the full-length cancer/testis Ag NY-ESO-1 to CTL unless formulated as either an immune complex (NY-ESO-1/IC) or with ISCOMATRIX adjuvant. We now demonstrate that NY-ESO-1/ICs induce cross-presentation of HLA-A2- and HLA-Cw3-restricted epitopes via a proteasome-dependent pathway. In contrast, cross-presentation of NY-ESO-1/ISCOMATRIX vaccine was proteasome independent and required the cytosolic protease tripeptidyl peptidase II. Trafficking studies revealed that uptake of ICs and ISCOMATRIX vaccine by DCs occurred via endocytosis with delivery to lysosomes. Interestingly, ICs were retained in lysosomes, whereas ISCOMATRIX adjuvant induced rapid Ag translocation into the cytosol. Ag translocation was dependent on endosomal acidification and IL-4-driven differentiation of monocytes into DCs. This study demonstrates that Ag formulation determines Ag processing and supports a role for tripeptidyl peptidase II in cross-presentation of CTL epitopes restricted to diverse HLA alleles.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work is part of the doctoral thesis of M.O. at the Ludwig-Maximilians-University (Munich, Germany). This work was supported by the Deutsche Krebshilfe (Max Eder Research Grant to M.S.), the Deutsche Forschungsgemeinschaft (Grant GK1202 to M.S. and S.E.), the FöFoLe Program of the Ludwig-Maximilians-University of Munich (to M.O.), a Program Grant from the Australian National Health and Medical Research Council (to E.M.) and the Ludwig Institute for Cancer Research. N.R. is an Australian National Health and Medical Research Council Industry fellow. E.M. is an employee of CSL Limited and an Honorary Senior Research Fellow of the Ludwig Institute for Cancer Research.
2 Address correspondence and reprint requests to Dr. Max Schnurr, Medizinische Klinik Innenstadt, University of Munich, Ziemssenstrasse 1, 80336 Munich, Germany. E-mail address: max.schnurr{at}med.uni-muenchen.de
3 Abbreviations used in this paper: DC, dendritic cell; IC, immune complex; TPPII, tripeptidyl peptidase II; ISCOM, immune-stimulating complexes; DOC, deoxycholic acid; pDC, plasmacytoid DC; MoDC, monocyte-derived DC; AAF-CMK, Ala-Ala-Phe-chloromethylketone; LAMP, lysosomal-associated membrane protein-1; EEA-1, early endosomal Ag.
4 The on-line version of this article contains supplemental material.
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