Prostate Stem Cell Antigen DNA Vaccination Breaks Tolerance to Self-antigen and Inhibits Prostate Cancer Growth
Prostate Stem Cell Antigen DNA Vaccination Breaks Tolerance to Self-antigen and Inhibits Prostate Cancer Growth
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DOI：
10.1038/mt.2009.66
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发表时间：
2009-06-01
影响因子：
12.4
通讯作者：
O'Sullivan, Gerald C.
中科院分区：
文献类型：
--
作者：
Ahmad, Sarfraz;Casey, Garrett;O'Sullivan, Gerald C.
前列腺干细胞抗原（PSCA）是一种在正常人前列腺中表达并在前列腺癌中过度表达的细胞表面抗原。前列腺癌中PSCA蛋白水平升高与肿瘤分期/分级增加相关，具有雄激素非依赖性，并且在骨转移中具有更高的表达。在这项研究中，PSCA基因分离的转基因小鼠前列腺腺癌细胞系（TRAMPC 1），并产生疫苗质粒构建体。该质粒PSCA（pmPSCA）通过肌内电穿孔（EP）递送，并在雄性C57 BL/6小鼠中诱导针对皮下TRAMPC 1肿瘤的有效抗肿瘤免疫应答。pmPSCA疫苗接种抑制肿瘤生长，导致治愈或存活期延长。类似地，疫苗抑制表达PSCA的B16 F10肿瘤的转移。对PSCA的Th-1型免疫被激活，表明对自身抗原的耐受性被打破。这种免疫是肿瘤特异性的，并且可以通过脾细胞的过继转移来转移。小鼠保持健康，并且没有证据表明正常组织中存在附带的自身免疫反应。鉴于人和小鼠PSCA之间存在显著的同源性，EP辅助递送pmPSCA引起强烈的特异性应答，并且可以在新辅助或辅助环境中提供安全有效的前列腺癌免疫控制。
Prostate stem cell antigen (PSCA) is a cell surface antigen expressed in normal human prostate and over expressed in prostate cancer. Elevated levels of PSCA protein in prostate cancer correlate with increased tumor stage/grade, with androgen independence and have higher expression in bone metastases. In this study, the PSCA gene was isolated from the transgenic adenocarcinoma mouse prostate cell line (TRAMPC1), and a vaccine plasmid construct was generated. This plasmid PSCA (pmPSCA) was delivered by intramuscular electroporation (EP) and induced effective antitumor immune responses against subcutaneous TRAMPC1 tumors in male C57 BL/6 mice. The pmPSCA vaccination inhibited tumor growth, resulting in cure or prolongation in survival. Similarly, the vaccine inhibited metastases in PSCA expressing B16 F10 tumors. There was activation of Th-1 type immunity against PSCA, indicating the breaking of tolerance to a self-antigen. This immunity was tumor specific and was transferable by adoptive transfer of splenocytes. The mice remained healthy and there was no evidence of collateral autoimmune responses in normal tissues. EP-assisted delivery of the pmPSCA evoked strong specific responses and could, in neoadjuvant or adjuvant settings, provide a safe and effective immune control of prostate cancer, given that there is significant homology between human and mouse PSCA.