Therapeutic Discovery In Situ Vaccination withCD204Gene-Silenced Dendritic Cell, not Unmodified Dendritic Cell, Enhances Radiation Therapy of Prostate Cancer

Given the complexity of prostate cancer progression and metastasis, multimodalities that target different aspects of tumor biology, for example, radiotherapy in conjunction with immunotherapy, may provide the best opportunities for promoting clinical benefits in patients with high-risk localized prostate cancer. Here, we show that intratumoral administration of unmodified dendritic cells (DC) failed to synergize with fractionated radiotherapy. However, ionizing radiation combined with in situ vaccination with DCs, in which the immunosuppressive scavenger receptor A (SRA/CD204) has been downregulated by lentivirusmediated gene silencing, profoundly suppressed the growth of two mouse prostate cancers (e.g., RM1 and TRAMP-C2) and prolonged the lifespan of tumor-bearing animals. Treatment of subcutaneous tumors with this novel combinatorial radioimmunotherapeutic regimen resulted in a significant reduction in distant experimental metastases. SRA/CD204-silenced DCs were highly efficient in generating antigen or tumorspecific T cells with increased effector functions (e.g., cytokine production and tumoricidal activity). SRA/ CD204 silencing-enhanced tumor cell death was associated with elevated IFN-g levels in tumor tissue and increased tumor-infiltrating CD8þ cells. IFN-g neutralization or depletion of CD8þ cells abrogated the SRA/CD204 downregulation-promoted antitumor efficacy, indicating a critical role of IFN-g–producing CD8þ T cells. Therefore, blocking SRA/CD204 activity significantly enhances the therapeutic potency of local radiotherapy combined with in situ DC vaccination by promoting a robust systemic antitumor immunity. Further studies are warranted to test this novel combinatorial approach for translating into improved clinical outcomes in patients with prostate cancer. Mol Cancer Ther; 11(11); 1–11. 2012 AACR.