ISCOMATRIX adjuvant combines immune activation with antigen delivery to dendritic cells in vivo leading to effective cross-priming of CD8+ T cells

• Published in: The Journal of immunology (1950) 2011-07, Vol.187 (1), p.55-63
• Main Authors: Duewell, Peter, Kisser, Ulrich, Heckelsmiller, Klaus, Hoves, Sabine, Stoitzner, Patrizia, Koernig, Sandra, Morelli, Adriana B, Clausen, Björn E, Dauer, Marc, Eigler, Andreas, Anz, David, Bourquin, Carole, Maraskovsky, Eugene, Endres, Stefan, Schnurr, Max
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - administration & dosage; Animals; Cancer Vaccines - administration & dosage; Cancer Vaccines - immunology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Cells, Cultured; Cholesterol - administration & dosage; Cholesterol - immunology; Cross-Priming - immunology; Cytotoxicity Tests, Immunologic - methods; Dendritic Cells - immunology; Dendritic Cells - metabolism; Drug Combinations; Female; Gene Knock-In Techniques; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Killer Cells, Natural - pathology; Lymph Nodes - immunology; Lymph Nodes - pathology; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Melanoma, Experimental - prevention & control; Mice; Mice, Inbred C57BL; Mice, Transgenic; Natural Killer T-Cells - immunology; Natural Killer T-Cells - metabolism; Natural Killer T-Cells - pathology; Ovalbumin - administration & dosage; Ovalbumin - immunology; Peptide Fragments - administration & dosage; Peptide Fragments - immunology; Phospholipids - administration & dosage; Phospholipids - immunology; Quillaja - immunology; Saponins - administration & dosage; Saponins - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1004114

Cancer vaccines aim to induce CTL responses against tumors. Challenges for vaccine design are targeting Ag to dendritic cells (DCs) in vivo, facilitating cross-presentation, and conditioning the microenvironment for Th1 type immune responses. In this study, we report that ISCOM vaccines, which consist of ISCOMATRIX adjuvant and protein Ag, meet these challenges. Subcutaneous injection of an ISCOM vaccine in mice led to a substantial influx and activation of innate and adaptive immune effector cells in vaccine site-draining lymph nodes (VDLNs) as well as IFN-γ production by NK and NKT cells. Moreover, an ISCOM vaccine containing the model Ag OVA (OVA/ISCOM vaccine) was efficiently taken up by CD8α(+) DCs in VDLNs and induced their maturation and IL-12 production. Adoptive transfer of transgenic OT-I T cells revealed highly efficient cross-presentation of the OVA/ISCOM vaccine in vivo, whereas cross-presentation of soluble OVA was poor even at a 100-fold higher concentration. Cross-presenting activity was restricted to CD8α(+) DCs in VDLNs, whereas Langerin(+) DCs and CD8α(-) DCs were dispensable. Remarkably, compared with other adjuvant systems, the OVA/ISCOM vaccine induced a high frequency of OVA-specific CTLs capable of tumor cell killing in different tumor models. Thus, ISCOM vaccines combine potent immune activation with Ag delivery to CD8α(+) DCs in vivo for efficient induction of CTL responses.