射频消融与PD-1单抗的协同抗肿瘤作用

发布时间：2018-09-12 07:15

【摘要】：射频消融(Radiofrequency ablation,RFA)是一种广泛应用于原发性肝癌、结直肠癌肝转移、非小细胞肺癌等恶性肿瘤的微创治疗方法。系列研究结果表明RFA能激活肿瘤抗原特异性T细胞免疫应答,我们的前期研究也证实消融裂解物能有效负载激活DC(Dentritic cells)。然而,消融所致的免疫反应不足以阻止肿瘤的复发,说明RFA诱导的T细胞活性不能长期维持。PD-L1(programmed death-ligand-1)是抑制T细胞活性的重要负性共刺激分子,广泛表达于多种肿瘤,其表达水平与T细胞浸润密切相关。PD-L1是否参与RFA激活的抗肿瘤免疫反应的调控尚未明确。本研究通过对小鼠移植瘤模型的实验研究,以及对接受RFA治疗的同时性结直肠癌肝转移患者进行回顾性病例对照研究,分析RFA后肿瘤微环境中T细胞免疫反应的演变,探讨RFA与PD-1单抗阻断的协同抗肿瘤作用。结果显示,在小鼠双侧背部荷瘤模型中,单侧肿瘤RFA治疗对对侧肿瘤产生短暂的抑制作用。对消融区外肿瘤微环境中免疫反应研究发现,RFA激活T细胞免疫应答的同时诱导了适应性免疫抑制形成,表现为:消融后期肿瘤浸润T细胞活化后失能、肿瘤微环境中调节性T细胞(Treg)与髓源性抑制细胞(MDSC)扩增、Th1型免疫应答向Th2转化以及PD-1/PD-L1表达上调。对同时性结直肠癌肝转移患者肝转移瘤RFA治疗前与治疗后原发灶组织标本免疫组化染色结果表明,RFA能激活消融区外肿瘤微环境中T细胞免疫反应,同时诱导PD-L1表达上调。在小鼠结肠癌移植瘤模型中证实RFA联合PD-1单抗阻断能增强T细胞免疫应答,并阻止RFA后效应T细胞(Teff)向Treg转化,抑制肿瘤内髓源性抑制细胞(MDSC)扩增;两者联合应用对消融区外显著抑制肿瘤生长,并显著延长小鼠生存时间。该研究为开展RFA联合PD-1/PD-L1阻断治疗的临床研究提供了理论依据。
[Abstract]:Radiofrequency ablation (Radiofrequency ablation,RFA) is a minimally invasive therapy for malignant tumors such as primary liver cancer, colorectal cancer, liver metastasis and non-small cell lung cancer. A series of studies have shown that RFA can activate tumor antigen-specific T cell immune responses, and our previous studies have confirmed that ablation lysates can effectively load activated DC (Dentritic cells). However, the immune response induced by ablation is not sufficient to prevent the recurrence of tumor, suggesting that the T cell activity induced by RFA can not be maintained for a long time. PD-L1 (programmed death-ligand-1) is an important negative costimulatory molecule that inhibits the activity of T cells and is widely expressed in many kinds of tumors. The expression level of PD-L1 is closely related to T cell infiltration. Whether PD-L1 is involved in the regulation of anti-tumor immune response activated by RFA is not clear. In this study, an experimental study of transplanted tumor model in mice and a retrospective case-control study on patients with liver metastases from colorectal cancer treated with RFA were conducted to analyze the evolution of T cell immune response in tumor microenvironment after RFA. To investigate the synergistic anti-tumor effect of RFA and PD-1 monoclonal antibody. The results showed that unilateral tumor RFA therapy had a transient inhibitory effect on contralateral tumor in bilateral dorsal tumor bearing model of mice. In the study of immune response in the tumor microenvironment outside the ablation area, it was found that RFA activated T cell immune response and induced adaptive immunosuppression. In tumor microenvironment, regulatory T cell (Treg) and myelogenous inhibitory cell (MDSC) amplified Th1-type immune response were transformed into Th2 and PD-1/PD-L1 expression was up-regulated. Immunohistochemical staining of liver metastases before and after RFA treatment in patients with liver metastasis from simultaneous colorectal cancer showed that RFA could activate the T cell immune response in the tumor microenvironment outside the ablation area and induce the up-regulation of PD-L1 expression. In mouse colon cancer transplanted tumor model, it was confirmed that RFA combined with PD-1 monoclonal antibody could enhance T cell immune response, prevent the transformation of effector T cell (Teff) to Treg after RFA, and inhibit (MDSC) amplification of medullary inhibitory cells in the tumor. The combined therapy significantly inhibited tumor growth and significantly prolonged the survival time of mice outside the ablation area. This study provides a theoretical basis for the clinical study of RFA combined with PD-1/PD-L1 blocking therapy.
【学位授予单位】：苏州大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R730.5

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