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 ␣-galactosylceramide IntroductionHematologic malignancies typically express the necessary machinery for eliciting antitumor immunity, such as costimulatory molecules, yet many tumors are poorly immunogenic. Therapeutic vaccination strategies that incorporate immune adjuvants are likely to enhance immune recognition and targeting of hematologic cancers, an example being in mice vaccinated against mouse lymphomas with whole tumor cells loaded with CpG adjuvant. 1 Natural killer T (NKT) lymphocytes represent an immune regulatory population with recognized capacity for inducing innate (eg, NK cells) and adaptive (eg, CD8 T cell) antitumor immunity, [2][3][4] by their unique ability to rapidly produce large quantities of cytokines on TCR ligation, in particular IFN-␥. 5,6 As a result, the synthetic CD1d-dependent NKT cell ligand ␣-galactosylceramide (␣-GalCer) has been used for its NKT cell-mediated immune adjuvant properties in anticancer therapies. [7][8][9][10] Initial attempts to stimulate NKT cells in situ were to simply infuse soluble ␣-GalCer, which briefly inhibited the tumor growth, but had limited effects on survival. 11,12 In addition, multiple injections of ␣-GalCer led to deleterious effects including long-term NKT cell functional anergy or unresponsiveness. 12 Subsequently, ␣-GalCer was loaded onto dendritic cells (DCs) as a vaccine. This approach induced more potent antitumor effects than soluble ␣-GalCer injections, mainly by prolonging NKT cell IFN-␥ production and preventing induction of NKT cell anergy, and was able to significantly improve the activity of the DC vaccine if coadministered with tumor antigens. 10,13,14 The cumbersome nature of inducing and expanding DC from patients' peripheral blood monocytes for autologous ␣-GalCerpulsed DC therapy stimulated the use of irradiated tumor cells as a vehicle to deliver ␣-GalCer in vivo. [15][16][17] Here a full complement of tumor antigens (including undefined ones) and ␣-GalCer are codelivered, thus allowing generation of innate immunity and potentially long-term tumor-specific T-cell adaptive immunity. In a prophylactic setting, whole tumor cells loaded with ␣-GalCer were able to protect mice against subsequent challenge with live tumor cells 15,16 and were also shown to be partially effective at inhibiting growth of established solid tumors 17 (S.R.M., K.S., M. Li, H.D., S.F. Ngiow, M.J.S., Transient Foxp3 ϩ regulatory T cell depletion enhances therapeutic anticancer vaccination targeting the immunestimulatory properties of NKT cells, manuscript submitted, August 2012), demonstrating the ability of this vaccine to work successfully in a The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by ...

Invariant NKT Cells Induce Plasmacytoid Dendritic Cell (DC) Cross-Talk with Conventional DCs for Efficient Memory CD8+ T Cell Induction

“…To maximally harness such immunological cascades, we established an efficient system using cells bearing a cell-associated Ag along with the iNKT cell ligand, a-galactosylceramide (a-GalCer). For example, we used iNKT ligand-loaded, tumor-associated Ag (TAA)-expressing CD1d + tumor cells (tumor/Gal) (19)(20)(21) or allogeneic fibroblasts loaded with a-GalCer transfected with TAA mRNA (16,22).…”

An autologous leukemia cell vaccine prevents murine acute leukemia relapse after cytarabine treatment

“…We identified several mechanisms by which C1498 cells could suppress immune responses, including increased proportions of Tregs and Other groups have also shown that a-GalCer-pulsed acute leukemia cells can be used as a prophylactic vaccine. By using the AML cell line AML-ETO9a, Mattarollo et al 23 showed that irradiated a-GalCer-pulsed AML cells prevented the development of AML in the prophylactic setting but only delayed progression when administered therapeutically, and Shimizu et al 29 demonstrated effective prophylactic vaccination by using the myelomonocytic WEHI-3B model. Our experiments extend these findings by elucidating immunosuppressive activities in established leukemia and indicating that protection against acute leukemia can also be invoked during remission after cytarabine chemotherapy.…”

“…23,47,63 Although CD1d is weakly expressed on C1498 cells and has been identified in other acute leukemic cell lines, including AML-ETO9a, 23 EL4, and WEHI-3B (L.R.A, unpublished data, June 14, 2014), we have previously demonstrated that a CD1d-negative a-GalCer-pulsed glioma vaccine can provide protection against glioma challenge. 25 We have also shown that CD1d-deficient DCs can transfer a-GalCer to host resident CD1d-expressing antigenpresenting cells in vivo to induce potent invariant NKT-cell activation, which likely reflects transfer of a-GalCer embedded within membranes of the injected cells.…”

“…21,22 The glycolipid a-galactosylceramide (a-GalCer) has recently been shown to be a useful adjuvant for whole tumor cell vaccination by eliciting stimulatory interactions between dendritic cells (DCs) and natural killer T (NKT) cells. [23][24][25][26] When DCs acquire cellular material from irradiated tumor cells that have been treated with a-GalCer, the protein content is presented as peptides via major histocompatibility complex (MHC) molecules to CD4 1 and CD8 1 T cells, whereas the a-GalCer is presented via the MHClike molecule CD1d to NKT cells. Interactions between DCs and NKT cells promote CD40 signaling, leading to DC activation, which increases the capacity of DCs to stimulate peptide-specific T cells.…”

“…Interactions between DCs and NKT cells promote CD40 signaling, leading to DC activation, which increases the capacity of DCs to stimulate peptide-specific T cells. 23,24 Significantly, vaccines comprising irradiated tumor cells pulsed with a-GalCer have been shown to be effective in murine models of hematopoietic malignancies, including acute myeloid leukemia (AML) and acute lymphoid leukemia, 23,27,28 and in other malignancies. 25,27,29 Cancer-associated immunosuppression can present a significant barrier to effective vaccine-based immunotherapy.…”