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研究生:謝嘉玲
研究生(外文):Chia-Ling Hsieh
論文名稱:GM-CSF細胞素腫瘤疫苗用於癌症治療之可行性研究
論文名稱(外文):GM-CSF-Transduced Tumor Vaccine:Application in an Animal Model of Cancer Therapy
指導教授:黃麗華黃麗華引用關係
指導教授(外文):Lih-Hwa Hwang
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:微生物學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:1999
畢業學年度:87
語文別:中文
論文頁數:220
中文關鍵詞:GM-CSF細胞素腫瘤疫苗免疫治療免疫抑制物
外文關鍵詞:GM-CSFtumor vaccineimmunotherapyimmunosuppressive factor
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本 論 文 意 在 探 討 利 用 腫 瘤 細 胞 表 現 細 胞 激 素 , 以 此 作 為 腫 瘤 疫 苗 , 用 來 治 療 腫 瘤 之 可 行 性 。 為 達 此 目 的 , 首 先 需 有 一 良 好 之 基 因 轉 殖 工 具 , 能 將 基 因 傳 送 到 癌 細 胞 內 , 並 有 效 的 表 達 出 來 , 在 此 次 研 究 中 所 選 用 的 是 反 轉 錄 病 毒 載 體 。 在 本 實 驗 室 先 前 已 構 築 一 能 表 現 雙 基 因 之 反 轉 錄 病 毒 載 體 , S1 , 然 而 S1 載 體 表 現 外 來 基 因 的 效 果 並 不 十 分 理 想 。 推 測 原 因 , 可 能 是 S1 載 體 會 藉 由 剪 接 機 制 轉 錄 出 兩 條 RNA 。 其 中 primary transcript 在 外 來 基 因 的 起 始 點 上 游 即 已 帶 有 病 毒 gag 蛋 白 質 的 起 始 譯 碼 , 故 常 造 成 蛋 白的 轉 譯 是 由 gag 之 起 始 譯 碼 開 始 。 其 中 不 乏 有 許 多 是 由 不 同 開 放 讀 架 (open reading frame) 所 接 合 成 的 融 合 蛋 白 。 而 唯 有 spliced RNA 才 有 機 會 轉 譯 出 正 常 之 外 來 蛋 白 質 , 故 而 大 大 降 低 了 外 來 蛋 白的產 量 。 因 此 本 論 文 的 第 一 部 份 實 驗 即 著 手 改 善 現 有 的 S1 反 轉 錄 病 毒 載 體 。 藉 由 將 gag 基 因 之 AUG 起 始 譯 碼的 突 變 ,製 得 另 一 新 型的 S2 雙 基 因 反 轉 錄 病 毒 載 體。 隨 後 再 選 用 五 種 不 同 的 轉 殖 基 因 來 測 試 S2 重 組 病 毒 載 體 的 轉 譯 能 力 。 結 果 證 實 , primary transcript 少 了 上 游 gag 的 起 始 譯 碼 , 確 實 大 大 提 升 了 轉 譯 外 來 基 因 的 效 率 。 因 為 這 樣 一 來 ,無 論 是 primary 或 是 spliced RNA , 皆 可 用 來 轉 譯 外 來 蛋 白 質 。 估 計 S2 重 組 病 毒 載 體 可 增 加 外 來 蛋 白 質 表 現 量 達 4~14 倍 之 多 。 這 類 表 現 外 來 基 因 的 能 力 極 佳 的 病 毒 載 體 , 將 有利 於 日 後 腫 瘤 疫 苗 之 癌 症 治 療 模 型 的 建 立 。
目 前 有 關 腫 瘤 疫 苗 的 研 究中, 已 有 不 少 的 文 獻 報 告 , 細 胞 素 基 因轉 殖 的腫 瘤 疫 苗 , 在 動 物 實 驗 中 確 能 有 效 地 清 除腫 瘤。 然 而 這 些 動 物 模 型 的 建 立 都 只侷 限 在 對 局 部 實 質 性腫 瘤 (solid tumor) 的 治 療。 本 論 文 的 第二 部 份 , 乃 探 討 以 一 BALB/c 老 鼠 RL♂1 T 細 胞 淋 巴 癌 (T cell leukemia) 為 研 究 對 象 , 利 用 第 一 部 分 實 驗 所 構 築 的 S2 bicistronic 反 轉 錄 病 毒 載 體 攜 帶 老 鼠 的 GM-CSF 細 胞 素 基 因 , 送 入 此 癌 細 胞 中 表 現 ,製 成 GM-CSF 腫 瘤 疫 苗 , 觀 察 如 此 的 腫 瘤 疫 苗 是 否 對 全 身 性 的 腫 瘤 亦 具 有 療 效 。 實 驗 結 果 顯 示 , 這 種 腫 瘤 疫 苗 不 但 可 以 在 老 鼠 身 上 產 生 全 身 性 及 長 效 性 的 抗 癌 反 應 來 預 防 腫 瘤 的 產 生 , 且 對 已 存 在 的 腫 瘤 , 不 論 是 皮 下 實 質 性 的 腫 瘤 , 或 是 循 環 性 的 淋 巴 癌 都 有 療 效 。 然 而 若 一 次 植 入 大 量 的 癌 細 胞 , 或 將 治 療 的 時 間 延 遲, 都 會 降 低 腫 瘤 疫 苗 的 治 療 效 果 。 此 外 也 發 現 在 治 療 無 效 的 老 鼠 的 脾 臟 細 胞 的 抗 癌 能 力 比 治 療 有 效 的 老 鼠 的 脾 臟 細 胞 為 差 。 然 而 這 些 細 胞 一 旦 經 過 體 外 刺 激 (in vitro stimulation) , 則 無 論 腫 瘤 疫 苗 治 療 的 成 效 如 何 ,抗 癌 T 細 胞 的 毒 殺 能 力 則 無 差 別 。 另 一 方 面 , 藉 由 系 統 性 的 組 織 切 片染 色 , 分 析 疫 苗 接 種 部 位 及 腫 瘤 生 長 部 位 浸 潤 細 胞 的 變 化 情 形 , 結 果 發 現 , 事 實 上 大 腫 瘤 附 近 也 有 不 少 CD8+ T 細 胞 的 浸 潤 。
是 故 , 由 不 少 現 今 的 文 獻 報 告 及 上 述 的 實 驗 結 果 發 現 , 細 胞 素 腫 瘤 疫 苗 的 療 效 與 腫 瘤 大 小 是 呈 反 比 的 關 係 。 這 種 無 法 清 除 大 腫 瘤 的 現 象 , 無 異對 人 類 癌 症 治 療 是 一 大 瓶 頸 。 因 此 本 論 文 的 第三 部 份 則 著 重 於 腫 瘤 疫 苗 對 大 腫 瘤 治 療 無 效 的 可 能 機 制 的 探 討 。 由 於 大 腫 瘤 無 法 清 除 可 能 是 浸 潤 在 腫 瘤 附 近 之 免 疫 作 用 細 胞 數 量 不 夠 之 所 致 , 故 嘗 試 將 腫 瘤 疫 苗 直 接 接 種 在 大 腫 瘤 部 位 , 但 結 果 仍 是 不 能 清 除 腫 瘤 。 但 若 改 以 大 量 活 化 過 的 抗 癌 T 細 胞 直 接 接 種 在 腫 瘤 位 置 , 則 可 以 把 已 存 在 的 大 腫 瘤 予 以 清 除 。 另 一 方 面 , 無 論 在 培 養 的 癌 細 胞 , 或 大 腫 瘤 部 位 的 組 織 中 , 可 以 測 得 到 免 疫 抑 制 性 細 胞 素 : 如 TGF-b , 和 IL-10 的 存 在 。 經 由 in vitro 的 實 驗 證 實 了 此 癌 細 胞 培 養 液 中 的 TGF-b 和 IL-10 , 的確 也 有 抑 制 抗 癌 T 細 胞 的 增 殖 能 力 。 在 in vivo 實 驗 中 , 額 外 施 打 癌 細 胞 培 養 液 於 小 腫 瘤 的 治 療 模 式 , 則 會 大 大 降 低 其 原 來 腫 瘤 疫 苗 的 療 效 。 綜 合 這 些 結 果 推 測 , 大 腫 瘤 能 躲 避 腫 瘤 疫 苗 所 引 起 的 免 疫 系 統攻 擊 的 原 因 至 少 存 在 有 兩 個 可 能 性 。 第一 : 有 功 能 之 腫 瘤 毒 殺 性 T 細 胞 對 癌 細 胞 數 目的 比 例 , 需 達 到 一 定 的 門 檻 才 能 有 效 地 清 除 腫 瘤 , 而 在 大 腫 瘤 老 鼠 體 內 , 腫 瘤 疫 苗 所 能 激 起 的 〝 有 功 能 〞 之 腫 瘤 毒 殺 性 T 細 胞 的 數 量 可 能 不 夠 , 故 無 法 清 除 大 量 的 癌 細 胞 。 第二 :腫 瘤 部 位 存 在 有 免 疫抑 制 物 , 降 低 了 毒 殺 性 T 細 胞 的活 性 。 當 腫 瘤 愈 大 此 種 抑 制 物 愈 多 , 致 使 抗 癌 T 細 胞 無 法 發 揮 正 常 功 能 。 根 據 上 述 結 果 推 論 , 本 實 驗 進 一 步 證 明 腫 瘤 所 分 泌 的 IL-10 , 可 能 是 直 接 抑 制 T 細 胞 在 活 化 時 介 白 素 二 號 接 受 子 (IL-2 receptor) 的 表 現 , 導 致 T 細 胞 無 法 活 化 完 全 ; 或 者 間 接 透 過 降 低 局 部 抗 原 呈 現 細 胞 表 面 分 子 , 如 MHC class I , B7 , 或 ICAM-1 的 表 現 , 而 使 得 浸 潤 至 腫 瘤 部 位 之 抗 癌 T 細 胞 缺 乏 進 一 步 的抗 原 呈 現 及 刺 激 , 而 無 法 發 揮正 常 毒 殺 癌 細 胞 的 功 能 導 致 治 療 失 效 。
總 結 而 論 , 目 前 細 胞 素 腫 瘤 疫 苗 若 要 直 接 應 用 於 惡 性 癌 症 病 人 的 治 療, 可 能 仍 有 一 段 距 離 。 但 其 引 發 全 身 性 且 長 效 性 的 免 疫 反 應 , 確 有 其 可 取 之 處 。 是 故 如 何 克 服 大 腫 瘤 無 法 被 細 胞 素 腫 瘤 疫 苗清 除 的 難 題 , 仍 有 待 於 我 們 日 後 對 其 機 制 有 更 深 入 的 瞭 解 時 予 以 解 決 。
In this study, we evaluated the feasibility of employing the cytokine-transduced tumor cells as a tumor vaccine for cancer treatment. The strategy needs a powerful gene transfer technique to deliver gene efficiently into cancer cells and results in a high level expression of transgene. For this purpose, the retroviral vector was employed as a high-efficiency gene-delivery system in this study. We have recently constructed a bicistronic retroviral vector, S1, and the transcriptional efficiency of the S1 bicistronic vector was as good as the single gene vector. However, in some cases, the relatively high level of transcripts produce only low amounts of protein. Therefore, in the first part of this study, a new bicistronic retroviral vector, S2, was constructed to improve the expression efficiency by removing a viral gag initiation codon that is retained in the S1 vector at 5'' to the first initiation codon of transduced gene. It was shown that the new bicistronic vector, S2, was able to increase the level of protein yield by 4~14 folds when compared with that of S1. Since the RNA levels and splicing patterns from these two vectors remained similar, the improvement was most likely resulted from the increased translational efficiency of the S2 vector. Thus, the modified S2 retroviral vector was then utilized for cancer therapy because of its high levels of expression.
Previous studies on tumor vaccine made containing granulocyte-macrophage colony-stimulating factor (GM-CSF) were all based on solid tumors. In the second part of this study, I used a murine T leukemia as a model to evaluate the efficacy of the GM-CSF-transduced tumor vaccine for the treatment of solid tumors as well as leukemias. By using the S2 bicistronic retroviral vector, mouse GM-CSF cDNA was transduced into a highly tumorigenic T leukemia cell line, RL♂1. Injection of GM-CSF-secreting RL♂1 cells into syngeneic BALB/c mice elicited a systemic and long-lasting immunity that prevented the tumor formation. The tumor vaccine also inhibited the growth of pre-established tumors that were introduced subcutaneously (solid tumor status) or intravenously (leukemia status) in animals. However, the therapeutic effects were less prominent in mice inoculated with a large tumor load or in mice treated later. Further basic immunological analysis supports the proposition that CD8+ T lymphocytes might have played an important role in rejecting the tumors in vivo. However, the CD8+ T lymphocytes of the animals bearing large tumors seemed to be suppressed or anergized. Systematic histological analysis for 2 weeks provided further insight into various infiltrates at the vaccine sites and at the tumor sites in response to the inoculation of GM-CSF-secreting tumor vaccine.
Despite the detection of tumor-specific CTL activities and CD8+ T cells in the large tumor-bearing mice treated with GM-CSF-transduced tumor vaccine, the immune cells did not confer protective effects upon the animals. Therefore in the third part of this study, the question how tumors manage to grow in the vicinity of activated CD8+ T cells was addressed. Firstly, it was found that adoptive transfer of a large number of activated CD8+ T cells into the tumor sites could regress tumors that had already been present for 7 days. Secondly, it was noted that the expression levels of immunosuppressive cytokines, TGF-b and IL-10, at the tumor region were correlated with the size of tumors. TGF-b and IL-10 were also detected in the culture supernatant of RL♂1 tumor cells. In vitro assay showed that co-cultivation of T cells with the culture supernatant of RL♂1 cells inhibited the tumor specific T cell proliferation. Inhibition TGF-b and IL-10 activity in the supernatant by antibody blocking abolished the immunosuppressive effects. Furthermore, pre-administration of the RL♂1 cultured supernatant or recombinant IL-10 into mice receiving the (1, 4)-treatment protocol greatly reduced the therapeutic effects of tumor vaccine. Taken altogether, these results suggest two possibilities that might explain how tumors escape from immune attract. The first possibility is that CTLs to tumor (C/T) ratio at the tumor location does not reach the threshold required for large tumor regression. The second is that the CTL activity in large tumor-bearing animal is suppressed by abundant immunosuppressive factors secreted by the tumors. Furthermore, the expression of surface maker on antibody-stimulated T cells or monocytes in the presence of tumor cell cultured supernatant was analyzed. The results showed that secretion of IL-10 by RL♂1 tumor cells may reduce T cell activation directly through inhibition of IL-2 receptor expression on T cells, or indirectly by down-regulation of the antigen presentation function of APC.
As a result, how to improve current tumor vaccine efficacy and overcome the immunosuppressive effects of tumor cells seem to be urgent tasks before the cytokine gene therapy can be applled as a treatment strategy for the patients bearing large tumor burdens
封面
標題
考試委員簽名頁
授權書
誌謝
中文摘要
英文摘要
目錄
縮寫
表目錄
圖目錄
第一章 導論
第一節 前言
第二節 腫瘤的免疫反應
一、腫瘤抗原
二 抗癌免疫反應之作用機制
三、T細胞的活化
四、腫瘤躲避宿主免疫系統攻擊之機制
第三節 腫瘤疫苗之免疫療法
一、提高腫瘤抗原呈現的機會
二、提高癌細胞MHC class I分子的表現
三、避免T細胞的不反應性
四、增加癌細胞和通細胞間的親和力
五、細胞素調節宿主的免疫機能
第四節 基因轉殖的方法
一、反轉錄病毒載體
二、腺病毒載體
三、單純皰疹病毒載體
四、直接DNA轉殖
第五節 反轉錄病毒載體導引的基因轉移
一、病毒的基因體和Proviral DNA的結構
二、病毒的生活史
三、反轉錄病毒載體
四、反轉錄病毒載體導引的基因轉移
第二章 雙基因反轉錄病毒載體之改良
第一節 前言
第二節 材料與方法
一、細胞的培養
二、S2反轉錄病毒載體的構築及核酸序列的分析
三、包含各種測定基因之質體的構築
四、重組反轉錄病毒的製備及感染
五、RNA之萃取與北方墨漬雜交分析
六、酵素連接免疫分析法
七、單純皰疹病毒胸腺嘧啶活化激素的活性測定
八、西方墨漬分析
第三節 結果
一、重組病毒RNA剪接的效率受殖入的核酸序列的不同而改變
二、改造過的病毒基因載體可提高外來基因的表現量
第四節 討論
第三章 老鼠GM-CSF細胞素基因轉殖之腫瘤疫苗對於老鼠淋巴癌之免疫治療
第一節 前言
第二節 材料與方法
一、細胞的培養
二、包含老鼠GM-CSF基因之反轉錄病毒載體的構築
三、重組反轉錄病毒的製備及RL1癌細胞株的感染
四、酵素連接免疫分析法
五、老鼠GM-CSF細胞素的活性測定
六、細胞表面分子的免疫螢光染色分析
七、動物實驗
八、毒殺性T細胞活性分析
九、組織學與免疫組織學的分析
第三節 結果
一、經老鼠GM-CSF基因轉殖之癌細胞株特性的分析
二、GM-CSF細胞素因的表現對腫瘤細胞癌化的影響
三、腫瘤疫苗對於老鼠淋巴瘤的療效
四、細胞性的免疫反應擔任清腄瘤的角色
五、組織學與免疫組織學分析
第四節 討論
第四章 GM-CSF細胞素因轉殖之腫瘤疫苗對於大腫瘤治療無效的可能機制之探討
第一節 前言
第二節 材料與方法
一、細胞的培養
二、RL1癌細胞培養液的製備與濃縮
三、腫瘤部位TGF-β及IL-10表現之分析
四、TGF-β1及-IL-10的酵素連接免疫分析
五、脾臟內T細胞的純化
六、腫瘤專一性T細胞的增殖
七、單核球細胞表面分子的免疫螢光染色分析
八、抗體制激之T細胞表面分子的免疫螢光染色分析
九、動物實驗
第三節 結果
一、腫瘤毒殺T細胞對癌細胞作用門檻之探討
二、癌細胞會產生免疫抑制物的探討
三、RL1細胞培養液對抗癌T細胞增殖的影響
四、不含血清之癌細胞培養液或IL-10在活體中的影響
五、不含血清之癌細胞培養液對抗原呈現細胞的影響
六、不含血清之癌細胞培養液對抗體刺激之T細胞活化的影響
第四節 討論
第五章 討論與展望
附表
附圖
參考文獻
附錄
一、實驗步驗
二、與本論文相關之已發表的文獻
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