CCL20 mediated onco-immuno-crosstalk in pancreatic cancer – translational intervention studies

CCL20 介导的胰腺癌中的肿瘤免疫串扰 â 转化干预研究

• 批准号: 414216991
• 负责人: Professor Dr. Alexander Arlt
• 金额: --
• 依托单位: Universitätsklinikum für Innere Medizin - Gastroenterologie, Hepatologie, Stoffwechselmedizin, Nieren- und Hochdruckerkrankungen
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/414216991?language=en
• 关键词: CCL20; mediated; onco; immuno; crosstalk

Pancreatic ductal adenocarcinoma (PDAC) exhibits one of the worst survival rates of all cancers. While in the majority of cancer, death rates show declining trends, PDAC register rising rates. For the majority of patients a “curative” intended resection is not feasible and the response rates to present chemo- and radiotherapeutic approaches remain highly unsatisfactory. One hallmark of PDAC is a profound desmoplastic stroma reaction consisting of fibroblasts, endothelial and immune cells as well as non-cellular components, essentially contributing to therapy resistance of PDAC. It is well established that inflammatory pathways play a major role in the development and progression of PDAC. We and others have shown that inflammation and tumorigenesis are functionally connected and controlled by the NF-kB signaling pathway, mediating apoptosis resistance. By using a genome wide unbiased approach we were able to establish the chemokines CCL20 as a central NF-kB target gene mediating therapy resistance. Our data show that CCL20 is acting in a paracrine fashion, leading to an increased recruitment of inflammatory cells. These inflammatory cells in turn mediate apoptosis resistance of PDAC cells. Therefore, our data dissect a bifunctional cross-signaling pathway in PDAC between tumor and immune cells important for therapeutic resistance. By the use of various complementary in vitro, ex vivo and in vivo models, we will further dissect the cancer-immune cell interaction and strengthen the value of such onco-immuno-crosstalks to tailor novel precise therapeutic interventions. In preliminary work we could broaden the spectrum to conventional chemotherapeutic drugs, which also induce the same CCL20 response (biphasic, unpublished data) recruiting immune cell which render the PDAC cell therapy resistant. Further dissection of the chemokine mediated onco-immuno-crosstalk is required to strengthen the value of this potential molecular target as a starting point in combined anti-tumor-therapy approaches in the future. The main objective of this project is a translational approach in murine and human in and ex vivo models to elaborate the clinical relevance of onco-immuno-crosstalk in PDAC with an initial focus on the chemokine CCL20. We aim to characterize the immune cells in greater detail using the simplified co-culture model to further understand the mechanisms involved in the CCL20 mediated onco-immuno-crosstalk (part I of the working program). Using an orthotopic syngeneic mouse model of PDAC and organoids derived from this model we will analyze the in vivo relevance for therapy resistance of onco-immuno crosstalk in murine PDAC (part II of the working program). Finally, we will establish human organoid-coculture systems as a platform for translational therapy testing (ongoing cooperation with Prof. Saur, PD Schneider and Dr. Reichert, TU Munich) from EUS guided biopsies of human PDAC in combination with peripheral PBMC of the same patients.

胰腺导管腺癌(PDAC)是所有癌症中存活率最低的癌症之一。虽然在大多数癌症中，死亡率呈下降趋势，但PDAC的死亡率却在上升。对于大多数患者来说，“根治性”切除是不可行的，对目前的化疗和放射治疗方法的反应率仍然非常不令人满意。PDAC的一个特征是由成纤维细胞、内皮细胞和免疫细胞以及非细胞成分组成的深度促结缔组织间质反应，这是导致PDAC治疗耐药的主要原因。炎症通路在PDAC的发生发展中起着重要作用，这是公认的事实。我们和其他人已经证明，炎症和肿瘤的发生在功能上是联系在一起的，并受核因子-kB信号通路的控制，介导细胞凋亡抵抗。通过使用全基因组无偏见的方法，我们能够将趋化因子CCL20建立为中心的核因子-kB靶基因，介导治疗耐药。我们的数据显示，CCL20以旁分泌的方式发挥作用，导致炎性细胞的募集增加。这些炎性细胞反过来介导PDAC细胞的凋亡抵抗。因此，我们的数据剖析了PDAC中肿瘤和免疫细胞之间的双功能交叉信号通路，这对治疗耐药非常重要。通过使用各种互补的体外、体外和体内模型，我们将进一步剖析癌症与免疫细胞的相互作用，并加强这种肿瘤免疫串扰的价值，以量身定制新的精确治疗干预措施。在初步工作中，我们可以将频谱拓宽到传统的化疗药物，这些药物也可以诱导相同的CCL20反应(双相，未发表的数据)，招募免疫细胞，使PDAC细胞治疗耐药。需要进一步剖析趋化因子介导的肿瘤免疫串扰，以加强这一潜在分子靶点作为未来联合抗肿瘤治疗方法的起点的价值。该项目的主要目标是在小鼠和人类体内和体外模型中进行翻译，以阐明PDAC中肿瘤免疫串扰的临床相关性，最初的重点是趋化因子CCL20。我们的目标是使用简化的共培养模型更详细地表征免疫细胞，以进一步了解CCL20介导的肿瘤免疫串扰(工作计划的第一部分)所涉及的机制。使用PDAC的同种异体原位小鼠模型和从该模型衍生的有机化合物，我们将分析在体内与小鼠PDAC肿瘤免疫串扰治疗耐药性的相关性(工作计划的第二部分)。最后，我们将建立人类器官共培养系统，作为转换治疗测试的平台(正在与德国慕尼黑大学的Saur教授、PD Schneider教授和Reichert博士合作)，结合相同患者的外周PBMC，在EUS引导下对人类PDAC进行活检。