TY - JOUR
T1 - NKT cell adjuvant-based tumor vaccine for treatment of myc oncogene-driven mouse B-cell lymphoma
AU - Mattarollo, Stephen R.
AU - West, Alison C.
AU - Steegh, Kim
AU - Duret, Helene
AU - Paget, Christophe
AU - Martin, Ben
AU - Matthews, Geoffrey M.
AU - Shortt, Jake
AU - Chesi, Marta
AU - Bergsagel, P. Leif
AU - Bots, Michael
AU - Zuber, Johannes
AU - Lowe, Scott W.
AU - Johnstone, Ricky W.
AU - Smyth, Mark J.
PY - 2012/10/11
Y1 - 2012/10/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84867795406&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867795406&partnerID=8YFLogxK
U2 - 10.1182/blood-2012-04-426643
DO - 10.1182/blood-2012-04-426643
M3 - Article
C2 - 22932803
AN - SCOPUS:84867795406
SN - 0006-4971
VL - 120
SP - 3019
EP - 3029
JO - Blood
JF - Blood
IS - 15
ER -