title: NKT cell adjuvant-based tumor vaccine for treatment of myc oncogene-driven mouse B-cell lymphoma.
abstract: Immunomodulators are effective in controlling hematologic malignancy by initiating or reactivating host antitumor immunity to otherwise poorly immunogenic and immune suppressive cancers. We aimed to boost antitumor immunity in B-cell lymphoma by developing a tumor cell vaccine incorporating α-galactosylceramide (α-GalCer) that targets the immune adjuvant properties of NKT cells. In the Eμ-myc transgenic mouse model, single therapeutic vaccination of irradiated, α-GalCer-loaded autologous tumor cells was sufficient to significantly inhibit growth of established tumors and prolong survival. Vaccine-induced antilymphoma immunity required NKT cells, NK cells, and CD8 T cells, and early IL-12-dependent production of IFN-γ. CD4 T cells, gamma/delta T cells, and IL-18 were not critical. Vaccine treatment induced a large systemic spike of IFN-γ and transient peripheral expansion of both NKT cells and NK cells, the major sources of IFN-γ. Furthermore, this vaccine approach was assessed in several other hematopoietic tumor models and was also therapeutically effective against AML-ETO9a acute myeloid leukemia. Replacing α-GalCer with β-mannosylceramide resulted in prolonged protection against Eμ-myc lymphoma. Overall, our results demonstrate a potent immune adjuvant effect of NKT cell ligands in therapeutic anticancer vaccination against oncogene-driven lymphomas, and this work supports clinical investigation of NKT cell-based immunotherapy in patients with hematologic malignancies.
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Australia. s.mattarollo@uq.edu.au
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Mattarollo
authors.forename: Alison C
authors.initials: AC
authors.lastname: West
authors.forename: Kim
authors.initials: K
authors.lastname: Steegh
authors.forename: Helene
authors.initials: H
authors.lastname: Duret
authors.forename: Christophe
authors.initials: C
authors.lastname: Paget
authors.forename: Ben
authors.initials: B
authors.lastname: Martin
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Matthews
authors.forename: Jake
authors.initials: J
authors.lastname: Shortt
authors.forename: Marta
authors.initials: M
authors.lastname: Chesi
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.forename: Michael
authors.initials: M
authors.lastname: Bots
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D019496:Cancer Vaccines / Q000627:therapeutic use*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000008:administration & dosage*; D019676:Genes, T-Cell Receptor delta / Q000502:physiology; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000502:physiology; D020382:Interleukin-18 / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D005699:Galactosylceramides; D020382:Interleukin-18; C493154:alpha-galactosylceramide; D018664:Interleukin-12; D007371:Interferon-gamma