title: Archaeosomes as self-adjuvanting delivery systems for cancer vaccines.
abstract: Archaeal ether glycerolipid vesicles (archaeosomes) efficiently deliver exogenous antigen for induction of humoral and cell-mediated immunity. Because induction of CD8 cytotoxic T cells is critical for protective vaccination against tumors, we compared the ability of various archaeosome lipid compositions to evoke a strong CD8 CTL response to entrapped antigen. Subcutaneous immunization of mice with ovalbumin (OVA) entrapped in all archaeosome lipid compositions evoked a primary (day 10) splenic CTL response indicating processing for MHC class I presentation. Interestingly, several polar lipid compositions from halophilic archaea were very potent to adjuvant this early CTL response. Despite this, the lytic units reduced substantially by weeks 6-7. More importantly, at >50 weeks, only Methanobrevibacter smithii and Thermoplasma acidophilum both rich in bipolar membrane-spanning caldarchaeols, demonstrated recall memory CTLs. Immunization of mice with OVA entrapped in M. smithii, Halobacterium salinarum or T. acidophilum vesicles provided prophylactic protection against challenge with OVA-expressing solid tumors at 6 weeks. Even a dose of 3 microg OVA in archaeosomes significantly delayed tumor growth. Tumor protection was also noted in a therapeutic design wherein OVA-archaeosomes were injected concurrent with the tumor challenge. Interestingly, antigen-free T. acidophilum but not antigen-free H. salinarum archaeosomes provided innate therapeutic protection. Vaccination with a CTL peptide epitope from the melanoma differentiation antigen, tyrosinase-related protein 2, in archaeosomes induced a protective CD8 response against B16OVA metastasis, indicating potential for targeting self, tumor antigens. Thus, lipid structural properties of archaea may differentially modulate primary, long-term and/or innate immunity, impacting adjuvant choice for vaccine design.
authors.affiliation: lakshmi.krishnan@nrc-cnrc.gc.ca
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Krishnan
authors.forename: G
authors.initials: G
authors.lastname: Dennis Sprott
mesh_terms: D000818:Animals; D001105:Archaea / Q000737:chemistry*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004337:Drug Carriers; D005260:Female; D007113:Immunity, Innate; D008055:Lipids / Q000737:chemistry* / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D010047:Ovalbumin / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D004337:Drug Carriers; D008055:Lipids; D010047:Ovalbumin