射頻消融與PD-1單抗的協(xié)同抗腫瘤作用
發(fā)布時間：2018-09-12 07:15
【摘要】：射頻消融(Radiofrequency ablation,RFA)是一種廣泛應用于原發(fā)性肝癌、結(jié)直腸癌肝轉(zhuǎn)移、非小細胞肺癌等惡性腫瘤的微創(chuàng)治療方法。系列研究結(jié)果表明RFA能激活腫瘤抗原特異性T細胞免疫應答,我們的前期研究也證實消融裂解物能有效負載激活DC(Dentritic cells)。然而,消融所致的免疫反應不足以阻止腫瘤的復發(fā),說明RFA誘導的T細胞活性不能長期維持。PD-L1(programmed death-ligand-1)是抑制T細胞活性的重要負性共刺激分子,廣泛表達于多種腫瘤,其表達水平與T細胞浸潤密切相關(guān)。PD-L1是否參與RFA激活的抗腫瘤免疫反應的調(diào)控尚未明確。本研究通過對小鼠移植瘤模型的實驗研究,以及對接受RFA治療的同時性結(jié)直腸癌肝轉(zhuǎn)移患者進行回顧性病例對照研究,分析RFA后腫瘤微環(huán)境中T細胞免疫反應的演變,探討RFA與PD-1單抗阻斷的協(xié)同抗腫瘤作用。結(jié)果顯示,在小鼠雙側(cè)背部荷瘤模型中,單側(cè)腫瘤RFA治療對對側(cè)腫瘤產(chǎn)生短暫的抑制作用。對消融區(qū)外腫瘤微環(huán)境中免疫反應研究發(fā)現(xiàn),RFA激活T細胞免疫應答的同時誘導了適應性免疫抑制形成,表現(xiàn)為:消融后期腫瘤浸潤T細胞活化后失能、腫瘤微環(huán)境中調(diào)節(jié)性T細胞(Treg)與髓源性抑制細胞(MDSC)擴增、Th1型免疫應答向Th2轉(zhuǎn)化以及PD-1/PD-L1表達上調(diào)。對同時性結(jié)直腸癌肝轉(zhuǎn)移患者肝轉(zhuǎn)移瘤RFA治療前與治療后原發(fā)灶組織標本免疫組化染色結(jié)果表明,RFA能激活消融區(qū)外腫瘤微環(huán)境中T細胞免疫反應,同時誘導PD-L1表達上調(diào)。在小鼠結(jié)腸癌移植瘤模型中證實RFA聯(lián)合PD-1單抗阻斷能增強T細胞免疫應答,并阻止RFA后效應T細胞(Teff)向Treg轉(zhuǎn)化,抑制腫瘤內(nèi)髓源性抑制細胞(MDSC)擴增;兩者聯(lián)合應用對消融區(qū)外顯著抑制腫瘤生長,并顯著延長小鼠生存時間。該研究為開展RFA聯(lián)合PD-1/PD-L1阻斷治療的臨床研究提供了理論依據(jù)。
[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.
【學位授予單位】：蘇州大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R730.5
本文編號：2238290
[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.
【學位授予單位】：蘇州大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R730.5
【參考文獻】
相關(guān)期刊論文 前1條
1 Wan-Qing Chen;Rong-Shou Zheng;Si-Wei Zhang;Hong-Mei Zeng;Xiao-Nong Zou;;The incidences and mortalities of major cancers in China, 2010[J];Chinese Journal of Cancer;2014年08期
，本文編號：2238290
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