冷冻消融联合TGF-β阻断治疗前列腺癌的有效性及相关机制研究

项目名称： 冷冻消融联合TGF-β阻断治疗前列腺癌的有效性及相关机制研究

项目编号： No.81471761

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 郭志

作者单位： 天津医科大学

项目金额： 73万元

中文摘要： 冷冻消融是治疗前列腺癌有效手段，但癌细胞免疫逃逸导致复发与转移仍是难点。我们前期研究证实:1)冷冻消融取得疗效的同时伴随Th1/Th2比值升高；2)动物实验研究发现冷冻消融杀伤前列腺肿瘤细胞的同时伴有DC的成熟与活化增加，引流淋巴结中CD8+T细胞增多，且特异性杀伤前列腺肿瘤细胞的能力增强，证明冷冻消融已调动机体抗肿瘤免疫反应。然而，我们临床研究发现冷冻消融后前列腺癌患者外周血中调节性T细胞数量和TGF-β含量较术前均明显增加,并持续至术后28天。由于增高的TGF-β可能通过多种途径建立免疫耐受微环境，促进癌细胞逃逸免疫监视，导致肿瘤复发。据此，本项目采用TGF-β单抗阻断其信号通路，证实冷冻消融联合TGF-β阻断治疗前列腺癌的有效性，为调节冷冻免疫提供新靶点，为深入研究冷冻免疫相关机制提供新线索。

中文关键词： C14_前列腺肿瘤；介入治疗；冷冻消融；转化生长因子β；免疫反应

英文摘要： Cryoablation is an important alternative for prostate cancer. However, the immune escape of tumor cells is the crux for recurrence or metastasis. 1) Our former results confirmed the therapeutic effect and revealed an increasing ratio of Th1/Th2. 2) Our animal experiments showed that the cryoablation for prostate cancer was able to induce the maturition and activation of DC, and increase the CD8+T cell numbers in draining lymph node, which could kill prostate cancer cell specially. All of the results clarified that the cryoablation stimulated the anti-tumor response. However, our clinical research found the obvious increasing of Tregs and TGF-β in peripheral blood after cryoablation. The serum TGF-β level continued to rise at 28 days after treatment, which revealed a immune tolerance microenvironment existed. The increased TGF-β could establish immune tolerance by various pathways. It will promote the immune escape and disease recurrence. Thus, we will focus on the inhibiting immune tolerance by TGF-β blocking,confirm the efficacy of cryoablation combined TGF-β blocking for prostate cancer. The ultimate aim is to provide new molecular target of cryo-immunological response and new clew for the mechnisms of cryo-immunological response.

英文关键词： prostate cancer;interventional therapy;cryoablation;transforming growth factor beta;immune response