Dendritic cells combined with tumor cells and α-galactosylceramide induce a potent, therapeutic and NK-cell dependent antitumor immunity in B cell lymphoma

Background: Invariant natural killer T (iNKT) cells are a small population of lymphocytes with unique specificity for glycolipid antigens presented by non-polymorphic CD1d receptor on dendritic cells (DCs). iNKT cells play a central role in tumor immunology since they are implicated in the coordination of innate and adaptive immune responses. These cells can be activated with the prototypic lipid alpha-galactosylceramide (alpha-GalCer), stimulating interferon gamma (IFN-gamma) production and cytokine secretion, which contribute to the enhancement of T cell activation. Methods: We evaluated the antitumor effect of a combination of dendritic cells (DCs) and tumor cells with the iNKT cell agonist a-GalCer in a therapeutic model of B cell lymphoma. iNKT, NK and T cell phenotype was determined by flow cytometry. Serum cytokines were analyzed by Luminex technology. Significant differences between survival curves were assessed by the log-rank test. For all other data, Mann-Whitney test was used to analyze the differences between groups. Results: This vaccine induced a potent (100% survival), long-lasting and tumor-specific antitumor immune response, that was associated with an increase of both Th1 cytokines and IFN-gamma secreting iNKT cells (4.59 +/- 0.41% vs. 0.92 +/- 0.12% in control group; p = 0.01) and T cells (CD4 IFN-gamma(+): 3.75 +/- 0.59% vs. 0.66 +/- 0.18% p = 0.02; CD8 IFN-gamma(+): 10.61 +/- 0.84% vs. 0.47 +/- 0.03% p = 0.002). Importantly, natural killer (NK) cells played a critical role in the antitumor effect observed after vaccination. Conclusions: This study provides clinically relevant data for the development of iNKT-cell based immunotherapy treatments for patients with B cell malignancies.