Programmed death ligand 1 (PD-L1) cell-intrinsic signaling in pancreatic cancer – Influence on tumor metabolism, microenvironment and disease progression

胰腺癌中的程序性死亡配体 1 (PD-L1) 细胞内在信号传导 â 对肿瘤代谢、微环境和疾病进展的影响

• 批准号: 398222819
• 负责人: Dr. Max Heckler
• 金额: --
• 依托单位: Klinik für Allgemein-, Viszeral- und Transplantationschirurgie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/398222819?language=en
• 关键词: Programmed; death; ligand; PD; L1

Pancreatical ductal adenocarcinoma (PDAC) is one leading cause of cancer related deaths worldwide. In the last few years immune checkpoint targeting therapies were associated with therapeutic advances in several cancers. Especially targeting of the Programmed death 1/Programmed death ligand 1 (PD-1/PD-L1) axis seems to have a beneficial impact. PD-L1 is expressed in human pancreatic cancers and the tumor microenvironment (TME) and may be involved in tumor progression. Interaction of PD-L1 and T cell-bound PD-1 leads to exhaustion and dysfunction of cytotoxic T cells. In addition, recent data suggest that PD-L1 has a major influence on the metabolic imbalance between tumor cells and the TME. The aim of this proposal is to elucidate the key role of PD-L1 cell intrinsic signaling in PDAC cells regarding tumor metabolism and T cell response. Our hypothesis will be approached as follows: 1) PD-L1 modified PDAC cells will be generated using CRISPR technology. The altered phenotype of the generated cells will be assessed using a broad immunologic and metabolic panel of assays. Both, surface culture and organoid culture will be performed. 2) Modified cell lines from (1) will be orthotopically implanted into wildtype mice to mimic the human PDAC phenotype. The impact of PD-L1 alterations on tumor progression and the tumor micro environment will be monitored and compared. The focus will be put on positron-emission-tomography/ computed tomography (PET/CT) imaging, survival statistics and the immunologic and metabolic phenotypes of the murine model. There is an urgent need for new strategies for PDAC treatment and early diagnosis of the disease. This project will make a substantial contribution to the understanding of PD-1/PD-L1 intrinsic signaling in PDAC and potentially influence multimodal future treatment of this devastating disease.

胰腺导管腺癌（PDAC）是全球癌症相关死亡的主要原因之一。在过去的几年中，免疫检查点靶向治疗与几种癌症的治疗进展有关。特别是靶向程序性死亡1/程序性死亡配体1（PD-1/PD-L1）轴似乎具有有益的影响。PD-L1在人胰腺癌和肿瘤微环境（TME）中表达，可能参与肿瘤进展。PD-L1和T细胞结合的PD-1的相互作用导致细胞毒性T细胞的耗竭和功能障碍。此外，最近的数据表明，PD-L1对肿瘤细胞和TME之间的代谢失衡具有重大影响。该提案的目的是阐明PD-L1细胞内在信号在PDAC细胞中关于肿瘤代谢和T细胞应答的关键作用。我们的假设如下：1）PD-L1修饰的PDAC细胞将使用CRISPR技术产生。将使用广泛的免疫学和代谢试验组评估所产生细胞的改变的表型。将进行表面培养和类器官培养。2)将来自（1）的修饰的细胞系原位植入野生型小鼠中以模拟人PDAC表型。将监测和比较PD-L1改变对肿瘤进展和肿瘤微环境的影响。重点将放在正电子发射断层扫描/计算机断层扫描（PET/CT）成像，生存统计和免疫和代谢表型的小鼠模型。目前迫切需要PDAC治疗和疾病早期诊断的新策略。 该项目将对PDAC中PD-1/PD-L1内在信号传导的理解做出重大贡献，并可能影响这种毁灭性疾病的多模式未来治疗。