Prostate cancer is one of the leading causes of cancer deaths, with no curative treatments once it spreads. Alternative therapies, including immunotherapy, have shown limited efficacy. Dendritic cells (DC) have been widely used in the treatment of various malignancies. DC capture antigens and move to the lymphoid organs where they prime naive T cells. Interaction between DC and T cells are most active in lymph nodes and suppression of DC trafficking to lymph nodes impairs the immune response. In this work, we aimed to study trafficking of DC in vivo via various routes of delivery, to optimize the effectiveness of DC-based therapy. A DC labeling system was developed using 1,1'-dioctadecyltetramethyl indotricarbocyanine Iodine for in vivo fluorescent imaging. DC harvested from C57B/6 mice were matured, labeled, and injected intravenously, subcutaneously, or intratumorally, with or without antigen loading with whole tumor lysate, into C57B/6 mice inoculated with RM-1 murine prostate tumor cells. Signal intensity was measured in vivo and ex vivo. Signal intensity at the tumor site increased over time, suggesting trafficking of DC to the tumor with all modes of injection. Subcutaneous injection showed preferential trafficking to lymph nodes and tumor. Intravenous injection showed trafficking to lungs, intestines, and spleen. Subcutaneous injection of DC pulsed with whole tumor lysate resulted in the highest increase in signal intensity at the tumor site and lymph nodes, suggesting subcutaneous injection of primed DC leads to highest preferential trafficking of DC to the immunocompetent organs.

Decreased expression of CTA by prostate cancer may be a means of escaping immune monitoring. Combination of epigenetic modifications and immunomodulation by 5-AzaC and lenalidomide increased tumor immunogenicity and enhanced DC function and may be used in the treatment of advanced prostate cancer. Prostate 77: 361-373, 2017. © 2016 Wiley Periodicals, Inc.

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The main objective of this experiment was to determine and study the effects of combining two epigenetic modifiers, 5-azacyticidine (5-AzaC) and SB939, on a RM-1 murine prostate cancer cell model. The effectiveness of this combination on prostate cancer cells has not been previously studied. The study was implemented on ex vivo cell models to gain a better understanding of the true effects of the combination therapy on prostate cancer cells. Two variations of the combination therapy were tested in this study, each with different concentrations of SB939 (100nm and 200nm). To determine the effectivity of the combination therapy on prostate cancer cells, three factors were measured: cell proliferation, cancer testis antigen (CTA) expression, and apoptosis rate. To measure cell proliferation, a cell proliferation assay was conducted, and absorption rate was measured through a 450 nm wavelength. CTA expression was measured through a quantitative polymerase chain reaction (quant-PCR). For this study, the expression rates of five CTAs were measured (TEX15, CEP55, CCNA1, P1A, SPA17). Apoptosis rate was measured through an Annexin-V assay, in which two markers, Annexin-V and 7-AAD, were used. We found that SB939 combined with 5-AzaC show highest efficacy compare to each drug alone in terms of inhibiting tumor cell proliferation, as well as inducing tumor cells apoptosis and enhancing tumor cell immunogenicity by the induction of the expression of CTAs. This combination proved to be effective in combating murine prostate cancer cells, and can potentially be effective within in vivo models due to its high toxicity to these cancer cells, and its ability to render prostate cancer more immunogenic.

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