项目来源

台湾省政府科研基金(GRB)

项目主持人

罗永鸿

项目受资助机构

台湾省台北荣民总医院胸腔委员会

项目编号

MOST107-2314-B075-041

立项年度

2018

立项时间

未公开

研究期限

未知 / 未知

项目级别

省级

受资助金额

900.00千元台币

学科

临床医学

学科代码

未公开

基金类别

基础研究/学术补助

关键词

肺癌 ; 环状核糖核酸 ; 淋巴细胞 ; 肋膜积液 ; 计划性细胞死亡蛋白-1 ; 免疫疗法 ; Lung cancer ; circular RNA ; lymphocyte ; pleural effusion ; programmed cell death protein-1(PD-1) ; immunotherapy

参与者

邱士华

参与机构

未公开

项目标书摘要：肺癌是全球癌症患者死亡的主要原因。肿瘤微环境能让淋巴球及骨髓细胞转变为免疫功能低下的状态。利用抑制免疫检查点来活化T细胞免疫力之免疫疗法於近年来被积极研究，发现到计划性细胞死亡蛋白-1之抑制剂对於肺癌有明确的治疗效力。虽然计划性细胞死亡蛋白-1在肿瘤组织的表现与相关之免疫疗法的疗效有关联性，但许多试验显示，即使缺乏计划性细胞死亡蛋白-1表现，有些肿瘤仍然对免疫疗法有反应。如此的结果显示，单用计划性细胞死亡蛋白-1的表现可能不是预测免疫疗法效力的最佳生物标记。环状核糖核酸被报导在肺癌的组织里面可以发现，和淋巴结的转移有关联性，也有研究显示和计划性细胞死亡蛋白-1的表现有关联性。因此，环状核糖核酸也可能为预测肺癌免疫治疗效力的生物标记之一。在此研究，肺癌病患的肿瘤组织检体、恶性肋膜积液、血液检体将被收集，用来评估免疫细胞，肿瘤细胞，与生物标记之间的关联性，以了解免疫系统的抗癌能力。此研究也探讨能够预测免疫疗法效果的潜在生物标记，包括环状核糖核酸、淋巴细胞免疫分型、与计划性细胞死亡蛋白-1的表现，其作用机转也将一并讨论。本研究也会探讨以环状核糖核酸作为肺癌治疗的标靶，以期能够提升肺癌病患的存活率。

Application Abstract: Lung cancer is the leading cause of death from cancer in Taiwan and throughout the world.Many studies indicated that the tumor microenvironment can modulate or inhibit anti-tumor immunity of the immune system through a variety of mechanisms,such as conversion of lymphocytes or myeloid cells into immunosuppressive status.Immunotherapy through immune checkpoint inhibition by blocking programmed cell death protein(PD)-1/PD-L1(PD-1 ligand)signaling pathway to restore patients’T cell immunity has revealed promising and significant efficacy in a variety of malignancies,including NSCLC.Many tumors without PD-L1 expression still responded to the treatment.As a result,the expression of PD-L1 may not be the optimal biomarker to predict the efficacy of immunotherapy.Therefore,the identification of best biomarkers that predict which patients will respond to immunotherapy is an urgent need.One novel type of long noncoding RNAs,circular RNAs(circRNAs),are endogenous,much more stable,and widely expressed in tissues,saliva,blood,and exosomes.CircRNAs consist of a circular loop with multiple microRNA(miRNA)binding sites,being known as miRNA response elements(MREs),and function as miRNA sponges by competing with endogenous RNA to regulate gene expression.A number of circRNAs exist in the nucleus of cells and constitute circRNA-miRNA-mRNA axes which involved in signaling pathway of cancer-related or non-cancer diseases,such as apoptosis,vasularization,invasion and metastasis,by regulating pathogenicity-related gene expression at the transcriptional or post-transcriptional level.It has been reported that increased expression of circRNA,circ-ITCH could inhibit the activation of the Wnt/β-catenin signaling pathway by acting as a sponge of miR-7 and miR-214,and then led to inhibition of tumor initiation,progression,and metastasis in lung cancer.Association between up-regulated circRNA 100876 in NSCLC and lymph node metastasis was also reported.Hsa_circ_0013958 was discovered as a sponge for miR-134,and upregulated oncogenic cyclin D1.According to these studies,circRNAs revealed potential for serving as diagnostic or predictive biomarkers of lung cancer.The regulatory role of McircRasGEF1B in immune response during macrophage activation has been reported.Hsa_circ_0020397 was demonstrated to inhibit the function of miR-138 and upregulated miR-138 targets,including PD-L1 in tumor cells.The detailed interaction between circRNAs and anti-tumor immunity remains to be elucidated.In this study,biological specimens,including,tumor tissue,malignant pleural effusion,and blood samples will be collected,and evaluated for the relation among immune cells,tumor cells and biomarkers in order to explore the antitumor activity of immune system.The potential biomarkers to predict the response of lung cancer treatment and immunotherapy,including circRNAs,immunophenotyping of lymphocytes,and expression of PD-L1 will be investigated.This study will also evaluate the use of circRNAs as potential therapeutic targets in the future.

项目受资助省

台湾省