Archaeosomes induce enhanced cytotoxic T lymphocyte responses to entrapped soluble protein in the absence of interleukin 12 and protect against tumor challenge.
Archaeosome adjuvants formulated as archaeal ether glycerolipid vesicles induce strong CD4(+) as well as CD8(+) CTL responses to entrapped soluble antigens. Immunization of mice with ovalbumin (OVA) entrapped in archaeosomes composed of the total polar lipids of Methanobrevibacter smithii resulted in a potent OVA-specific CD8(+) T-cell response, and subsequently, the mice dramatically resisted solid tumor growth of OVA-expressing EG.7 cells and lung metastasis of B16OVA melanoma cells. Prophylactic protection was antigen-specific because tumor curtailment was not seen in mice injected with antigen-free archaeosomes. Similarly, there was no protection against B16 melanoma cells lacking OVA expression. Furthermore, in vivo depletion of CD8(+) T cells abrogated the protective response, indicating that the antitumor immunity was mediated by CTLs. Depletion of CD4(+) T cells also resulted in partial loss of tumor protection, suggesting a beneficial role for T-helper cells. Interestingly OVA-archaeosomes induced enhanced CTL response in the absence of interleukin 12 and IFN-gamma. Furthermore, interleukin 12-deficient mice mounted strong tumor protection. However, IFN-gamma-deficient mice, despite the strong CTL response, were only transiently protected, revealing a need for IFN-gamma response in tumor protection. Archaeosomes also facilitated therapeutic protection when injected into mice concurrent with tumor cells. Interestingly, even archaeosomes lacking entrapped antigen mediated therapeutic protection, and this correlated to the activation of innate immunity as evident by the increased tumor-infiltrating natural killer and dendritic cells. Thus, archaeosomes represent effective tumor antigen delivery vehicles that can mediate protection by activating both innate as well as acquired immunity.
Krishnan
Lakshmi
L
Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, K1A 0R6 Canada. lakshmi.krishnan@nrc-cnrc.gc.ca
Sad
Subash
S
Patel
Girishchandra B
GB
Sprott
G Dennis
GD
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D007371:Interferon-gamma / Q000172:deficiency / Q000276:immunology; D018664:Interleukin-12 / Q000172:deficiency* / Q000276:immunology; D008081:Liposomes / Q000276:immunology; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary / Q000628:therapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D017013:Methanobacteriaceae / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D008081:Liposomes; D018664:Interleukin-12; D007371:Interferon-gamma; D010047:Ovalbumin