放射治療與腫瘤免疫反應

Radiation Therapy and Tumor Immunology: Clinical Tumor Microenvironment and Oncolytic Virus Application

陳婉瑜(Wan-Yu Chen)

指導教授 ： 鄭安理 ； 鄭文芳 ； 郭頌鑫

國立臺灣大學/醫學院/臨床醫學研究所/博士(2022年)

https://doi.org/10.6342/NTU202200016

摘要

本論文研究結合溶瘤病毒和放射線治療。放射治療是癌症治療的重要一環，而溶瘤病毒為癌症免疫治療的一個新方向。溶瘤病毒除了腫瘤消融之外，能促進腫瘤微環境的改變，增加免疫細胞浸潤。研究結合溶瘤病毒和放射線治療對於臨床應用有實際價值。本研究使用免疫健全老鼠模型，研究結合高劑量立體定位放射治療(SBRT)和溶瘤痘苗病毒(vaccinia virus)，探討此合併療法的抗腫瘤效果和免疫機轉。研究結果顯示合併高劑量立體定位放射治療和溶瘤痘苗病毒可增加動物體內抗腫瘤效果，增加脾臟之CD4+Ki-67+幫手T細胞和CD8+Ki-67+殺手T細胞。合併療法也會增加腫瘤內浸潤CD3+CD4+幫手T細胞和CD3+CD8+殺手T細胞且降低調控T細胞(regulatory T cells)。並且，合併療法增強體外細胞死亡，部分經由細胞程序性壞死(necroptosis)而釋放出損害相關分子模式( damage-associated molecular patterns, DAMPs)，並改變巨噬細胞M1/M2的比例。此合併高劑量立體定位放射治療和溶瘤痘苗病毒的療法可做癌症臨床治療的參考。

關鍵字

放射治療 ； 溶瘤病毒 ； 腫瘤免疫

並列摘要

This thesis investigated combination of oncolytic virus and radiation therapy. Ra-diation is an integral part of cancer therapy. Oncolytic virus therapy is a novel cancer immune therapy. Oncolytic virus results in not only tumor lysis but also immune cells infiltration in tumor microenvironment. With the emergence of oncolytic vaccinia virus immunotherapy, it is important to study the combination of radiation and vaccinia virus in cancer therapy. In this study, we investigated the anti-tumor effect of and immune mechanisms underlying the combination of high-dose hypofractionated stereotactic body radiotherapy (SBRT) and oncolytic vaccinia virus in preclinical murine models. The combination enhanced the in vivo anti-tumor effect and increased the numbers of splenic CD4+Ki-67+ helper T lymphocytes and CD8+Ki-67+ cytotoxic T lymphocytes. Combinational therapy also increased tumor-infiltrating CD3+CD4+ helper T lympho-cytes and CD3+CD8+ cytotoxic T lymphocytes, but decreased tumor-infiltrating regula-tory T cells. In addition, SBRT combined with oncolytic vaccinia virus enhanced in vitro cell death, partly through necroptosis, and subsequent release of damage-associated mo-lecular patterns (DAMPs), and shifted the macrophage M1/M2 ratio. We concluded that SBRT combined with oncolytic vaccinia virus can trigger tumor cell necroptosis and modify macrophages through the release of DAMPs, and then generate potent an-ti-tumor immunity and effects. Thus, combined therapy is potentially an important strategy for clinical cancer therapy.

並列關鍵字

Radiation therapy ； oncolytic virus ； cancer immunotherapy

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