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

胰腺导管腺癌（PDAC）是所有癌症中生存率最低的癌症之一。虽然在大多数癌症中，死亡率呈下降趋势，但PDAC登记率上升。对于大多数患者，“治愈性”预期切除术是不可行的，目前的化疗和放疗方法的反应率仍然非常不令人满意。PDAC的一个标志是由成纤维细胞、内皮细胞和免疫细胞以及非细胞组分组成的深刻的促结缔组织增生基质反应，其基本上促成了PDAC的治疗抗性。众所周知，炎症途径在PDAC的发生和进展中起主要作用。我们和其他人已经表明，炎症和肿瘤发生在功能上是连接和控制的NF-κ B信号通路，介导细胞凋亡抵抗。通过使用全基因组无偏方法，我们能够将趋化因子CCL 20确定为介导治疗抗性的中心NF-kB靶基因。我们的数据显示，CCL 20以旁分泌方式起作用，导致炎症细胞的募集增加。这些炎性细胞进而介导PDAC细胞的凋亡抗性。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，这对治疗耐药性很重要。通过使用各种互补的体外，离体和体内模型，我们将进一步剖析癌症-免疫细胞相互作用，并加强这种肿瘤-免疫-串扰的价值，以定制新的精确治疗干预措施。在初步工作中，我们可以将范围扩大到常规化疗药物，其也诱导相同的CCL 20应答（双相，未公开的数据），募集免疫细胞，这使得PDAC细胞疗法具有抗性。需要进一步解剖趋化因子介导的肿瘤免疫串扰，以加强这种潜在的分子靶点作为未来联合抗肿瘤治疗方法的起点的价值。该项目的主要目的是在鼠和人体内和离体模型中的翻译方法，以阐述PDAC中肿瘤免疫串扰的临床相关性，最初关注趋化因子CCL 20。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CCL 20介导的肿瘤免疫串扰（工作计划的第一部分）中涉及的机制。使用PDAC的原位同基因小鼠模型和源自该模型的类器官，我们将分析鼠PDAC中肿瘤免疫串扰的治疗抗性的体内相关性（工作程序的第II部分）。最后，我们将建立人类器官共培养系统，作为转化疗法测试的平台（正在与Saur教授、PD Schneider和Reichert博士、TU慕尼黑合作），从EUS引导的人PDAC活检联合相同患者的外周PBMC。

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.