在惡性腦瘤樹突狀細胞療法中調控調節性T細胞活性的研究

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題名:	在惡性腦瘤樹突狀細胞療法中調控調節性T細胞活性的研究
作者:	邱紹智(Shao-Chih Chiu);周德陽(Der-Yang Cho);謝鐸源
貢獻者:	醫學院免疫學研究所;中國附醫神經精神醫學中心
日期:	2012-07-31
上傳時間:	2012-06-15 11:40:27 (UTC+8)
摘要:	?性腦瘤(GBM)為中樞?經系統中最常?也是?性?最高、癒後最差的腫瘤，以目前?床治?方法，病患存活時間平均僅僅只有12個月，通常88％的患者會在3?內死亡；因此找出有效的方式?治??性腦瘤，是目前?床研究的重點。許多?床試驗及前期研究上（包括我們?床研究團隊的?床第二期試驗初步結果），?用樹突?細胞（DC）的免疫?法可有效使體內產生抗腫瘤的能?並減緩腫瘤的進程。然而，搭配DC免疫?法的?性腦瘤治?在?床實驗?據加上人體免疫系統的複雜性，嘗試改善DC免疫?法的成果是一直被重視且投入大?研究人?的?域。愈?愈多研究顯示在?性腦瘤患者中，調節性T細胞（Treg）的存在或產生會嚴重抑制DC免疫?法的抗腫瘤免疫反應的結果。我們初步結果證實，Tregs能浸潤至?性腦瘤腫瘤組織中，而這些Tregs會以選擇性剪接作用產生出三種表現??同的FOXP3 isoform蛋白。由於FOXP3蛋白是Treg 專一性表現的關鍵功能蛋白，而且FOXP3的功能可以決定Treg 的免疫抑制效能的強?，我們發現浸潤至?性腦瘤腫瘤中的Treg所表現的Foxp3 isoforms 中，其中一個竟然是具有dominant negative的特性，也就是?引發這種isoform的表現，即會造成Foxp3原本的免疫抑制功能喪失! 這個發現提供?一個嶄新的配合?法方向，讓我們能?用調控剪接作用的機制使Foxp3擇先產生dominant negative isoform，如此達到有效的?低Treg抑制DC免疫?法的負作用，而?影響其他免疫系統的正常運作!在我所提出的計畫中，我將結合分析?床研究團隊的DC免疫?法的試驗結果，去探討研究Treg免疫抑制細胞在?性腦瘤進?DC免疫?法時所扮演的角色，並結合我先前在小分子化合物調控基因剪接作用的經驗，提供能強化免疫治?的成效的可能機制；同時我們也將建?一個以篩選Foxp3 dominant negative isoform的實驗平台，進?化合物的篩選。這個計畫的執?的重點目標如下：（一）、分析?性腦瘤組織中Treg所含?同Foxp3 isoform的表現?並與DC免疫?法?床試驗結果整合，建?關?性。（二）、研究Foxp3三種?同isoform免疫調控功能上的差?，並研究在DC?法中對腫瘤免疫反應的影響。（三）、探討具有調控剪接作用的?床藥物或小分子化合物是否會減低從腫瘤浸潤?巴球?的Treg的免疫抑制活性。（四）、評估目標三所找出之藥物調控Treg活性與DC免疫?法結合作用後對?性腦瘤治?的影響。我們初步的結果已顯示，經由比較Tregs所表現三種Foxp3 isoforms 的相對?，可以提供?性腦瘤腫瘤患者在接收DC免疫?法的預後指標! 本次計畫最主要的目的是結合?床試驗的結果，去評估經由操控Foxp3 isoform的表現?對Treg活性產生作用後，合併對?性腦瘤DC免疫?法的影響。我們相信，這些研究成果?但能提供?即可?能強化?性腦瘤DC免疫?法的輔助方法，也將有助於DC免疫?法在其他應用上的發展，並且在基礎研究的範疇中，能提供對Treg 細胞如何調節其功能的重要機轉! Glioblastoma multiforme (GBM) is the most frequent and most malignant high-grade glioma; in spite of improved surgical and combined radiochemotherapy techniques, the prognosis of patients with GBM remains poor, with a median survival at about 12 months, and 88% mortality within 3 years. Development of new and GBM specific therapies is thus a field of most fervent research. Numerous pre-clinical and clinical studies, including our own phase II clinical trial, demonstrated that Dendritic Cell-therapies (DC-therapies) can induce potent anti-tumor activity and diminish tumor progression. However, complete clinical responses have been rare, and the improvement of DC-therapy is the focus of intensive effort. Increasing evidence suggests that the presence or induction of regulatory T-cells (Tregs), may limit the efficacy of DC-therapy strategies by suppressing anti-tumor immune responses. In our preliminary studies, we have confirmed the presence of Tregs in GBM tumor infiltrating lymphocytes (TILs), and that these Tregs express 3 different isoforms of the FOXP3 gene by alternative splicing. Interestingly, one of the isoforms that we have identified represents a naturally occurring dominant negative version of the Foxp3 protein. Since the Foxp3 is the most important determinant for Treg immunosuppressive activity, functional abrogation by tuning the splicing preference of Foxp3 to the dominant negative isoform thus offer an attractive window to inhibit Treg activity. In the present grant application, we propose to test the hypotheses that Tregs play a critical role in limiting DC-therapy against GBM, and that the modulation of Treg activity by alternative splicing may result in improved therapeutic efficacy. We will establish the experimental foundation for this approach and to enable a direct test for compounds that may suppress Treg activity through altering the mRNA splicing of the FOXP3 gene. Our specific aims are as follows: (1). to establish the relationship between Treg immunosuppressive activity with clinical outcomes of DC-therapy of GBM; (2). to investigate the functional implications of differential expression of the 3 isoforms of Foxp3; (3). to explore whether splicing modulatory compounds can attenuate TIL-derived Treg activity; (4). to evaluate the effects of combined splicing modulation of Treg activity in DC-therapy of GBM. The grant we proposed will provide the basis for the in vivo evaluation of the effectiveness of combined Treg modulation (for the alteration of tumor immunity) with DC-therapies for GBM, and to elucidate the regulation of Treg activity through Foxp3 expression. These results will help establish immediately feasible adjuvant modulations to DC-therapy for GBM and other tumors, as well as to shed light on new mechanistic insights on how Treg function can be regulated.
顯示於類別:	[免疫學研究所] 研究計畫

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