To induce a potent cytotoxic T lymphocyte (CTL) response in dendritic cell (DC)-based immunotherapy against prostate cancer, various tumour antigens should be loaded onto DCs. The aim of this study was to establish a method of immunotherapy for castration-resistant prostate cancer (CRPC) using prostate cancer-specific CTLs generated in vitro by DCs. Monocyte-derived DCs from patients with CRPC were induced to mature using a standard cytokine cocktail (in IL-1b, TNF-a, IL-6 and PGE 2 : standard DCs, sDCs) or using an a-type 1-polarized DC (aDC1) cocktail (in IL-1b, TNF-a, IFN-a, IFN-c and polyinosinic: polycytidylic acid) and loaded with the UVB-irradiated CRPC cell line PC-3. Antigen-loaded DCs were evaluated by morphological and functional assays. The aDC1s significantly increased the expression of several molecules related to DC maturation, regardless of whether the aDC1s were loaded with tumour antigens or not, compared to sDCs. The aDC1s showed a higher production of interleukin-12 both during maturation and after subsequent stimulation with CD40L, which was not significantly affected by loading with tumour antigens, as compared to standard DCs (sDCs). Prostate cancer-specific CTLs against autologous CRPC cells were successfully induced by aDC1s loaded with dying PC-3 cells. Autologous aDC1s loaded with an allogeneic CRPC cell line can generate greater CRPC-specific CTL responses as compared to sDCs and may provide a novel source of DC-based vaccines that can be used for the development of immunotherapy in patients with CRPC.
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Signal transducers and activators of transcription 3 (STAT3) is highly activated in multiple myeloma triggered by IL-6. Although DC vaccine can induce antitumor immune response, DCs are faced with dysfunction after loading of tumor antigen. Here we show that the dysfunction of DCs from antigen loading can be recovered by treating JSI-124 and bortezomib on myeloma cells. Treatment of combination JSI-124 and bortezomib induced high expression of heat shock protein 90 (Hsp90) on the surface of dying myeloma cells, DCs loaded these myeloma cells showed low expression of p-STAT3 and reduced IL-10, IL-6 and IL-23 production without any effect on IL-12p70. Also DCs loaded with dying myeloma cells treated by JSI-124 and bortezomib combination could generate the most potent myeloma-specific CTLs targeting to myeloma cells. Our data suggested that treatment of myeloma cells with combination JSI-124 and bortezomib can recover the dying myeloma cells-loaded DC dysfunction through the highly expressed Hsp90 on tumor cells, down-regulated p-STAT3 and inhibitory cytokines, and these DCs can generate to potent myeloma-specific CTLs for obtaining better immunotherapeutic method in multiple myeloma.
Disclosures:
Lee: Vaxcell-Bio therapeutics Co.: Employment. Kim:Vaxcell-Bio therapeutics Co.: Employment. Lim:Vaxcell-Bio therapeutics Co.: Employment. Lee:Vaxcell-Bio therapeutics Co.: Employment.
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