Garcia-Hernandez Maria de la Luz, Gray Andrew, Hubby Bolyn, Klinger Otto J, Kast W Martin
Department of Molecular Microbiology and Immunology and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90033, USA.
Cancer Res. 2008 Feb 1;68(3):861-9. doi: 10.1158/0008-5472.CAN-07-0445.
Prostate stem cell antigen (PSCA) is an attractive antigen to target using therapeutic vaccines because of its overexpression in prostate cancer, especially in metastatic tissues, and its limited expression in other organs. Our studies offer the first evidence that a PSCA-based vaccine can induce long-term protection against prostate cancer development in prostate cancer-prone transgenic adenocarcinoma mouse prostate (TRAMP) mice. Eight-week-old TRAMP mice displaying prostate intraepithelial neoplasia were vaccinated with a heterologous prime/boost strategy consisting of gene gun-delivered PSCA-cDNA followed by Venezuelan equine encephalitis virus replicons encoding PSCA. Our results show the induction of an immune response against a newly defined PSCA epitope that is mediated primarily by CD8 T cells. The prostates of PSCA-vaccinated mice were infiltrated by CD4-positive, CD8-positive, CD11b-positive, and CD11c-positive cells. Vaccination induced MHC class I expression and cytokine production [IFN-gamma, tumor necrosis factor-alpha, interleukin 2 (IL-2), IL-4, and IL-5] within prostate tumors. This tumor microenvironment correlated with low Gleason scores and weak PSCA staining on tumor cells present in hyperplastic zones and in areas that contained focal and well-differentiated adenocarcinomas. PSCA-vaccinated TRAMP mice had a 90% survival rate at 12 months of age. In contrast, all control mice had succumbed to prostate cancer or had heavy tumor loads. Crucially, this long-term protective immune response was not associated with any measurable induction of autoimmunity. The possibility of inducing long-term protection against prostate cancer by vaccination at the earliest signs of its development has the potential to cause a dramatic paradigm shift in the treatment of this disease.
前列腺干细胞抗原（PSCA）是一种颇具吸引力的可用于治疗性疫苗靶向的抗原，因为它在前列腺癌中过度表达，尤其是在转移组织中，而在其他器官中的表达有限。我们的研究首次证明，基于PSCA的疫苗能够在易患前列腺癌的转基因腺癌小鼠前列腺（TRAMP）小鼠中诱导针对前列腺癌发展的长期保护作用。对表现出前列腺上皮内瘤变的8周龄TRAMP小鼠，采用异源初免/加强策略进行接种，即先用基因枪递送PSCA-cDNA，随后用编码PSCA的委内瑞拉马脑炎病毒复制子进行加强免疫。我们的结果显示，针对一个新定义的PSCA表位诱导了免疫反应，该反应主要由CD8 T细胞介导。接种PSCA疫苗的小鼠前列腺中有CD4阳性、CD8阳性、CD11b阳性和CD11c阳性细胞浸润。接种疫苗诱导了前列腺肿瘤内MHC I类分子的表达和细胞因子的产生[干扰素-γ、肿瘤坏死因子-α、白细胞介素2（IL-2）、IL-4和IL-5]。这种肿瘤微环境与增生区以及含有局灶性和高分化腺癌区域的肿瘤细胞低Gleason评分和弱PSCA染色相关。接种PSCA疫苗的TRAMP小鼠在12月龄时的存活率为90%。相比之下，所有对照小鼠均死于前列腺癌或肿瘤负荷很重。至关重要的是，这种长期的保护性免疫反应与任何可检测到的自身免疫诱导无关。在前列腺癌发展的最早迹象时通过接种疫苗诱导针对前列腺癌的长期保护作用，有可能在这种疾病的治疗中引起巨大的模式转变。
