THE ANTITUMOR ACTIVITY OF DENDRITIC CELLS MATURED IN THE PRESENCE OF TOLL-LIKE RECEPTOR’S LIGANDS AND INTERFERONS

The ability of dendritic cells (DCs) to induce tumor-specific T-cells has been used in immunotherapy of a cancer more than 20 years, but the clinical efficacy of the DCs remains limited. Crucial importance in obtaining mature cells belongs to the composition and the concentration of the components of the cocktail for maturation, which in the `standard` version includes a combination of cytokines: TNFα, IL-6, IL-1β и PGE2. However, in this environment DCs do not actively produce IL-12p70 that sharply reduces their polarizing potential towards the Th1 immune response. The key role in this negative effect plays PGE2. In this research, has been created a new maturation cocktail based on Toll-like receptor agonists that induce the maturation of DCs capable of in-ducing a Th1 response. A comparative analysis was also conducted with DCs obtained by the “standard protocol” in terms of: proliferative response of T-cells in the mixed culture of lymphocytes, secretion of IL-12p70 and IL-10 by DCs, the expression profile of costimulatory molecules of DCs and the chem-otaxis of naïve T-cells in vitro. The cytokine cocktail, including interferons and TLR ligands, provides a mature phenotype of DC, a prevalence of costimulatory molecules over coinhibitor, active migration and proliferation of T cells, and high secretion of IL-12p70 in response to CD40L stimulation. In the mixed culture of lympho-cytes, these signals shift the polarization of the immune response towards IFNγ-secreting Th1 cells with suppression of concomitant activation of regulatory T cells. This maturation protocol, in contrast to standard DC vaccines, allows obtaining a culture of αDC1, the cells of which combine all the necessary, even contradictory, properties of antitumor vaccines.