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

• Applicant: Professor Dr. Alexander Arlt
• Subject Area: Gastroenterology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 414216991

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could broaden the spectrum to conventional chemotherapeutic drugs, which also induce the same CCL20 response (biphasic, unpublished data) recruiting immune cell which render the PDAC cell therapy resistant.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.

• DFG Programme: Research Grants