Cyclophosphamide and IL-12-transduced DCs enhance the antitumor activity of tumor antigen-stimulated DCs and reduce Tregs and MDSCs number.

Summary: A hostile tumor microenvironment, characterized by anabundance of T regulatory cells and myeloid-derived suppressorcells (MDSCs), considerably limits the efficacy of dendritic cell(DC)-based vaccines. The intention of this study was to enhancethe antitumor activity of vaccines consisting of bone marrow-derived DCs stimulated with TAg (BMDC/TAg) via singleadministration of cyclophosphamide and multiple injections ofinterleukin (IL)-12-transduced DCs (BMDC/IL-12). The combinedchemoimmunotherapy was applied in the treatment of mice withsubcutaneously (SC) growing, advanced MC38 colon carcinoma.The highest level of tumor growth inhibition, accompanied by highcytotoxic activity of effector cells, and their increased influx intotumor tissue, was observed after application of cyclophosphamidein combination with BMDC/TAg and BMDC/IL-12. The effectwas probably associated with the elimination of T regulatory cellsfrom spleens and tumors, but most of all with changes in thenumber and differentiation stage of MDSCs. After the therapy, thepercentage of granulocytic and monocytic MDSCs in spleens wassignificantly lower than in the control group. Moreover, MDSCsderived from spleens and tumors showed increased expression ofMHC class II, which may indicate the higher maturation stage ofthe myeloid cells as well as their enhanced capacity toward antigenpresentation. The obtained data indicate that the optimal compo-sition of antitumor vaccines able to limit the suppressor activity ofMDSCs is essential to enhance the elimination of tumor cells andto achieve an optimal therapeutic effect.Key Words: antitumor immunotherapy, experimental MC38 coloncarcinoma, cyclophosphamide, IL-12-transduced dendritic cells,myeloid-derived suppressor cells