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 lentivirus-mediated 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
tumor-specific 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-γ levels in
tumor tissue and increased
tumor-infiltrating CD8(+) cells. IFN-γ neutralization or depletion of CD8(+) cells abrogated the SRA/CD204 downregulation-promoted antitumor efficacy, indicating a critical role of IFN-γ-producing CD8(+) 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.