Abstract
Many studies have demonstrated that prostate stem cell antigen (PSCA) is an attractive target for immunotherapy based on its overexpression in prostate tumor tissue, especially in some metastatic tissues. In this study, we evaluated dendritic cell (DC)-directed lentiviral vector (DCLV) encoding murine PSCA (DCLV-PSCA) as a novel tumor vaccine for prostate cancer in mouse models. We showed that DCLV-PSCA could preferentially deliver the PSCA antigen gene to DC-SIGN-expressing 293T cells and bone marrow-derived DCs (BMDCs). Direct immunization with the DCLV-PSCA in male C57BL/6 mice elicited robust PSCA-responsive CD8+ and CD4+ T cells in vivo. In a transgenic adenocarcinoma mouse prostate cell line (TRAMP-C1) synergetic tumor model, we further demonstrated that DCLV-PSCA-vaccinated mice could be protected from lethal tumor challenge in a prophylactic model, whereas slower tumor growth was observed in a therapeutic model. This DCLV-PSCA vaccine also showed efficacy in inhibiting tumor metastases using a PSCA-expressing B16-F10 model. Taken together, these data suggest that DCLV is a potent vaccine carrier for PSCA in delivering anti-prostate cancer immunity.
Highlights
In 2011, the FDA approved the first therapeutic cancer vaccine for treatment of asymptomatic or slightly symptomatic hormone refractory prostate cancer [1,2], a great encouragement for both prostate cancer patients and scientists working on cancer immunotherapy
The cells were collected for expression of prostate stem cell antigen (PSCA) by fluorescence-activated cell sorter (FACS) analysis. 293T cells transfected with the FUW-PSCA plasmid showed positive expression of PSCA (22.5%), while cells transfected with the FUW-Null plasmid had only background staining (Figure 1A)
Our results indicated that DCLVPSCA could target dendritic cell (DC)-SIGN-expressing cells and deliver the PSCA antigen to DCs in vitro
Summary
In 2011, the FDA approved the first therapeutic cancer vaccine for treatment of asymptomatic or slightly symptomatic hormone refractory prostate cancer [1,2], a great encouragement for both prostate cancer patients and scientists working on cancer immunotherapy. Several antigens have been identified as potential immunotherapy candidates for prostate cancer vaccines. They include the prostate-specific antigen (PSA) [6], prostate stem cell antigen (PSCA) [7,8,9,10], prostate-specific membrane antigen (PSMA) [11], prostatic acid phosphatase (PAP) [2], mucin 1 (MUC1) [12], gonadotropin-releasing hormone (GnRH) [13], and NY-ESO-1 vaccine [14], among others. Antibody directed to PSCA has been tested to inhibit prostate cancer tumor growth and suppress metastasis formation [20], while others have investigated chimeric antigen receptors (CAR)based adoptive T cells therapy targeting PSCA for its potential in treating prostate cancer [21]. Experiments have been conducted to test PSCA as a vaccine antigen, and it has been clearly shown in animal models that PSCA-targeted vaccines can slow down prostate cancer progression [22,23]
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