NKT cell adjuvant-based tumor vaccine for treatment of myc oncogene-driven mouse B-cell lymphoma

Stephen R. Mattarollo, Alison C. West, Kim Steegh, Helene Duret, Christophe Paget, Ben Martin, Geoffrey M. Matthews, Jake Shortt, Marta Chesi, P. Leif Bergsagel, Michael Bots, Johannes Zuber, Scott W. Lowe, Ricky W. Johnstone, Mark J. Smyth

Research output: Contribution to journalArticle

44 Scopus citations

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 AMLETO9a 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 oncogenedriven lymphomas, and this work supports clinical investigation of NKT cell-based immunotherapy in patients with hematologic malignancies.

Original languageEnglish (US)
Pages (from-to)3019-3029
Number of pages11
JournalBlood
Volume120
Issue number15
DOIs
StatePublished - Oct 11 2012

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Mattarollo, S. R., West, A. C., Steegh, K., Duret, H., Paget, C., Martin, B., Matthews, G. M., Shortt, J., Chesi, M., Bergsagel, P. L., Bots, M., Zuber, J., Lowe, S. W., Johnstone, R. W., & Smyth, M. J. (2012). NKT cell adjuvant-based tumor vaccine for treatment of myc oncogene-driven mouse B-cell lymphoma. Blood, 120(15), 3019-3029. https://doi.org/10.1182/blood-2012-04-426643