In situ vaccination with CD204 gene-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 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.
Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, PO Box 980033, Richmond, VA 23298, USA.
Chunqing
C
Guo
Huanfa
H
Yi
Xiaofei
X
Yu
Daming
D
Zuo
Jie
J
Qian
Gary
G
Yang
Barbara A
BA
Foster
John R
JR
Subjeck
Xiaolei
X
Sun
Ross B
RB
Mikkelsen
Paul B
PB
Fisher
Xiang-Yang
XY
Wang
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D016923:Cell Death; D045142:Cross-Priming / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D020868:Gene Silencing; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control / Q000532:radiotherapy*; D034741:RNA, Small Interfering / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016896:Treatment Outcome; D014611:Vaccination
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; C495140:Msr1 protein, mouse; D034741:RNA, Small Interfering; D051117:Scavenger Receptors, Class A; D007371:Interferon-gamma