Abstract
Recent data on the application of dendritic cells (DCs) as anti-tumor vaccines has shown their great potential in therapy and prophylaxis of cancer. Here we report on a comparison of two treatment schemes with DCs that display the models of prophylactic and therapeutic vaccination using three different experimental tumor models: namely, Krebs-2 adenocarcinoma (primary tumor), melanoma (B16, metastatic tumor without a primary node) and Lewis lung carcinoma (LLC, metastatic tumor with a primary node). Dendritic cells generated from bone marrow-derived DC precursors and loaded with lysate of tumor cells or transfected with the complexes of total tumor RNA with cationic liposomes were used for vaccination. Lipofectamine 2000 and liposomes consisting of helper lipid DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and cationic lipid 2D3 (1,26-Bis(1,2-de-O-tetradecyl-rac-glycerol)-7,11,16,20-tetraazahexacosan tetrahydrocloride) were used for RNA transfection. It was shown that DCs loaded with tumor lysate were ineffective in contrast to tumor-derived RNA. Therapeutic vaccination with DCs loaded by lipoplexes RNA/Lipofectamine 2000 was the most efficient for treatment of non-metastatic Krebs-2, where a 1.9-fold tumor growth retardation was observed. Single prophylactic vaccination with DCs loaded by lipoplexes RNA/2D3 was the most efficient to treat highly aggressive metastatic tumors LLC and B16, where 4.7- and 10-fold suppression of the number of lung metastases was observed, respectively. Antimetastatic effect of single prophylactic DC vaccination in metastatic melanoma model was accompanied by the reductions in the levels of Th2-specific cytokines however the change of the levels of Th1/Th2/Th17 master regulators was not found. Failure of double prophylactic vaccination is explained by Th17-response polarization associated with autoimmune and pro-inflammatory reactions. In the case of therapeutic DC vaccine the polarization of Th1-response was found nevertheless the antimetastatic effect was less effective in comparison with prophylactic DC vaccine.
Highlights
One novel therapeutic approach to curing cancer is to enlist the body’s natural defence mechanisms and recruit key contributors to the immune response
Stimulation of dendritic cells (DCs) with 2D3/RNA resulted in five-fold increase of CD80+ cells together with 1.6-fold increase of mean fluorescence intensity (MFI) and three-fold increase of CD83+ cells accompanied by slight increase of MFI in comparison with non-stimulated DCs (Fig 1B, compare w/s and 2D3/RNA panels)
In this work we studied prophylactic and therapeutic anti-tumor vaccines based on DCs loaded with tumor RNA or cell lysate
Summary
One novel therapeutic approach to curing cancer is to enlist the body’s natural defence mechanisms and recruit key contributors to the immune response. Immature DCs are pulsed with tumour antigens in the form of peptides [5], proteins [6], tumour cell lysates [7], apoptotic [8, 9] or live [10] tumour cells, as well as viral vectors [11,12,13] and nucleic acids (NA) encoding TAA [14] ex vivo and re-administered to the recipient, where DCs migrate into peripheral lymph nodes and spleen and initiate the activation of anti-tumor T and B cell immune responses. In 2010 the first USA FDA approval ever of a therapeutic DC-based cancer vaccine, Sipuleucel-T, to treat advanced castration-resistant prostate cancer was granted [24]
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