Cellular immunotherapy for b-cell lymphoma with nkt-cell agonists

Resumo

Natural killer T (NKT) cells are a small population of lymphocytes with unique specificity for glycolipid antigens presented by non-polymorphic CD1d receptor on APC, mainly presented on dendritic cells (DCs). NKT cells play a central role in tumor immunology since they coordinate innate and adaptive immune responses. These cells can be activated with the prototypic lipid α-galactosylceramide (α-GalCer), stimulating IFN-γ production and cytokine secretion (eg, IL-12, IL-4, IL-17) that contribute to the enhancement of DC function and the induction of NK, B and T-cell activation. We evaluated the antitumor effect of a combination of DCs and irradiated tumor cells with the NKT cell agonist α-GalCer in a mouse model of B-cell lymphoma. The therapeutic vaccine consisting of DCs, tumor cells and α-GalCer was able to eradicate B-cell lymphoma in all treated mice, and was superior to any vaccine combination, including α-GalCer alone, irradiated tumor cells with DCs, and DCs with α-GalCer. Importantly, treated mice with the vaccine were resistant to a tumor rechallenge, suggesting the development of a memory immune response. In addition, the immune response was tumor-specific since all the mice were unable to reject a syngeneic A20 B-cell lymphoma. In addition to in vivo evaluation of the therapeutic vaccine, the cytokine profile induced by the treatment was evaluated, showing a combination of Th1 and Th2 cytokines together with IL-17. When we looked at effector cells, we observed that the vaccine induces a high NKT and NK-cell expansion, as well as a high increase of IFN-γ secreting NKT, NK and tumor-specific T cells. NK cells played a critical role in the antitumor effect observed after the therapeutic treatment and there was also an activation of B cells since IgG antibodies against tumor cells were found in treated mice. The therapeutic vaccine consisting of dendritic cells, tumor cells and α-GalCer efficiently eradicates B-cell lymphoma in a therapeutic setting. This immune response is long-lasting, tumor-specific, and it is associated with an expansion of NK and NKT cells, an increase of IFN-γ secreting NK, NKT and T cells and B-cell activation.