INFLUENCE OF PGE2 AND LIGANDS OF TOLL-LIKE RECEPTORS ON THE IMMUNOLOGICAL PROPERTIES OF THE MATURE DENDRITIC CELLS ASSOCIATED WITH THEIR ANTITUMOR ACTIVITY
Dendritic cells, acting as professional antigen-presenting agents, are capable of inducing tumor-specific T-cell immunity, which causes a continuing interest in their use in cancer immunotherapy, despite the fact that the clinical efficacy of such protocols remains limited. The composition and concentration of the components of the cocktail for the maturation of DC is crucial for their future characteristics. The "gold standard" can be considered a combination of cytokines, including TNFa, IL-1ß, IL-6 and PGE2. This cocktail in small variations of the composition was used in most clinical studies, where mature DCs were used as adaptive immunotherapy. However, in terms of the maturation of DCs, including this combination of cytokines, IL-12p70 is not produced, which is of particular importance for the polarization of the immune response in the direction of Th1, which is most needed for an effective response against tumor cells. A key role in this negative effect is played by PGE2, which blocks the production of IL-12p70 and simultaneously induces the production of an antagonist of IL-12R, an IL-12p40 homodimer. The cytokine cocktail for maturation of DCs in vitro, including interferons and ligands of Toll-like receptors, considered in this study, ensures the formation of a mature DC phenotype, the predominance of costimulatory molecules over the co-inhibitory molecules, and a high level of TL-12p70 secretion, in response to CD40L stimulation, which is different from protocols that include the PGE2 cytokine cocktail, which has an overwhelming effect on the proliferation of T-cells. However, paradoxical was the fact that PGE2 enhances the expression of CCR7, which in turn enhances the chemotaxis of DC in response to the chemokines CCL19 and CCL21. Tn the present study, an attempt was made to explain the paradoxical property of PGE2 to induce increased expression of CCR7 on the sDC surface and simultaneously reduce the production of CCL19 and create a protocol for the maturation of DC, which will make it possible to obtain a culture of aDC1, whose cells simultaneously combine all the necessary and often contradictory properties shown to anticancer vaccines