2018-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/680708摘要：合成生物學雖仍處在新興發展的階段，卻已應用在許多研究領域並帶來長足的貢獻，包含許多生技與醫藥領域。 在此計畫中，我將嘗試建立一種應用於免疫檢查點治療之的創新方法，此乃是使用合成生物學之技術將細菌改造為抗癌載體，並能夠對抗癌細胞所產生的免疫抑制機制(program cell death receptor 1, and the corresponding ligand 1; PD-1/PD-L1)，進而再活化免疫系統，藉以消滅腫瘤。此細菌將被編程為智慧元件，具有自動感測腫瘤之能力，並能特定聚集在腫瘤而非其他正常組織，繼而在腫瘤之微環境中開始作用。此細菌元件可藉由局部性的降低腫瘤之免疫抑制反應以恢復免疫能力。更具體地來說，我們將益生菌E. coli strain Nissle 1917 基因重組，使得它能夠感測腫瘤微環境或者腫瘤相關免疫信號分子(例如：interferon-γ)。一旦感測到目標，此細菌元件便可在腫瘤微環境中合成重組胜&#32957;片段 rPD-1，用以遮蔽位於腫瘤細胞上之PD-L1。藉此，腫瘤將無法透過PD1/PD-L1 之機制來抑制免疫反應，進而達到治癒癌症之目標。 此細菌元件具有免疫監控與調控之能力，故可作為癌症治療檢測之平台，藉以在腫瘤周圍局部提昇免疫力，並同時減低引發其他部位甚至全身性自體免疫問題。因此，用此細菌元件以提昇局部免疫反應之方式可望成為一種較安全且有效之癌症治療方法。 <br> Abstract: As an emerging discipline at its infancy stage, synthetic biology has already given great promises on advancing broad spectrum of research fields, ranging from agriculture, bioenergy, bioremediation, biomaterials as well as biomedicine. Cellular engineering with incorporated genetic elements carrying therapeutic functionality, for instance, can often render successful outcomes for health improvement and disease protection. In the proposal, I aim to harness the power of synthetic biology to transform the bacteria into cancer fighters that can battle with the defense system of tumor as a novel means toward immune checkpoint therapy. The bacteria will be programmed into smart devices that autonomously home to, sense and actuate in the tumor microenvironments. Such bacterial devices, in turn, can locally recharge the immunity by counterbalancing cancer cells’ immunosuppression mediated through PD-1/PD-L1 mechanism. More specifically, probiotic E. coli strain Nissle 1917 is genetically rewired to sense tumor associated factors, such as immune signaling molecule, interferon-γ in the tumor microenvironments. Upon sensing, the bacteria device is then able to synthesize the therapeutic rPD-1 peptide fragment into tumor microenvironments, masking PD-L1 sites on cancer cells. In the end, the tumors will lose the chance to interactively suppress the immunity through PD-1/PD-L1 mechanism, leading to ultimately tumor eradication. The bacteria devices, with the engineered immunosurveillance and modulation capability, can serve as the potential cancer theranostic platform that leads to not only locally-promoted immunity in tumor vicinity but also reduced systematic autoimmunity in distal area, which might be beneficial as a safe and effective cancer therapeutic agent.合成生物學細菌癌症免疫檢查點治療法PD-1/PD-L1synthetic biologybacteriacancerimmune checkpoint therapyPD-1/PD-L1