title: ISCOMATRIX vaccines mediate CD8+ T-cell cross-priming by a MyD88-dependent signaling pathway.
abstract: Generating a cytotoxic CD8(+) T-cell response that can eradicate malignant cells is the primary objective of cancer vaccine strategies. In this study we have characterized the innate and adaptive immune response to the ISCOMATRIX adjuvant, and the ability of vaccine antigens formulated with this adjuvant to promote antitumor immunity. ISCOMATRIX adjuvant led to a rapid innate immune cell response at the injection site, followed by the activation of natural killer and dendritic cells (DC) in regional draining lymph nodes. Strikingly, major histocompatibility complex (MHC) class I cross-presentation by CD8α(+) and CD8α(-) DCs was enhanced by up to 100-fold when antigen was formulated with ISCOMATRIX adjuvant. These coordinated features enabled efficient CD8(+) T-cell cross-priming, which exhibited prophylactic and therapeutic tumoricidal activity. The therapeutic efficacy of an ISCOMATRIX vaccine was further improved when co-administered with an anti-CD40 agonist antibody, suggesting that ISCOMATRIX-based vaccines may combine favorably with other immune modifiers in clinical development to treat cancer. Finally, we identified a requirement for the myeloid differentiation primary response gene 88 (MyD88) adapter protein for both innate and adaptive immune responses to ISCOMATRIX vaccines in vivo. Taken together, our findings support the utility of the ISCOMATRIX adjuvant for use in the development of novel vaccines, particularly those requiring strong CD8(+) T-cell immune responses, such as therapeutic cancer vaccines.
authors: Department of Molecular Oncology, Genentech Inc, South San Francisco, CA 94080, USA.
authors: Nicholas S
authors: NS
authors: Wilson
authors: Becky
authors: B
authors: Yang
authors: Adriana Baz
authors: AB
authors: Morelli
authors: Sandra
authors: S
authors: Koernig
authors: Annie
authors: A
authors: Yang
authors: Stefanie
authors: S
authors: Loeser
authors: Denise
authors: D
authors: Airey
authors: Larissa
authors: L
authors: Provan
authors: Phil
authors: P
authors: Hass
authors: Hal
authors: H
authors: Braley
authors: Suzana
authors: S
authors: Couto
authors: Debbie
authors: D
authors: Drane
authors: Jeff
authors: J
authors: Boyle
authors: Gabrielle T
authors: GT
authors: Belz
authors: Avi
authors: A
authors: Ashkenazi
authors: Eugene
authors: E
authors: Maraskovsky
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000951:Antigens, Neoplasm / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D002784:Cholesterol / Q000008:administration & dosage / Q000276:immunology*; D045142:Cross-Priming / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004338:Drug Combinations; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D010743:Phospholipids / Q000008:administration & dosage / Q000276:immunology*; D020239:Receptor Cross-Talk / Q000187:drug effects; D012503:Saponins / Q000008:administration & dosage / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D019013:CD40 Antigens; D019496:Cancer Vaccines; D004338:Drug Combinations; C493786:ISCOMATRIX; D053594:Myeloid Differentiation Factor 88; D010743:Phospholipids; D012503:Saponins; D010047:Ovalbumin; D002784:Cholesterol