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

• Final Report Year: 2024

Final Report Abstract

The main objective of this project was a translational approach in murine and human in and ex vivo models to elaborate the clinical relevance of onco-immune-crosstalk in PDAC with an initial focus on the chemokine CCL20. We aimed to characterize the immune cells in detail using the simplified coculture model to further understand the mechanisms involved in the CCL20-mediated onco-immune-crosstalk. Hereby we were able to show that PDAC cells recruit immune cells through CCL20 and activate a TH17 response. We were able to show that the immune cells produce and secrete IL-17a and blocking IL-17 abolished the apoptosis protection through supernatants of PBMC. Finally, by using recombinant IL-17 we were able to mimic the PMBC supernatant-mediated protection of PDAC cells. Using an orthotropic syngeneic mouse model of PDAC with different CCL20 signaling competent and mutated settings in the mouse and/or the implanted PDAC cells we were able to confirm an in vivo relevance for therapy resistance of CCL20-mediated onco-immune crosstalk in murine PDAC. Finally, we tried to establish human organoid-coculture systems as a platform for translational therapy testing from EUS guided biopsies of human PDAC in combination with peripheral PBMC of the same patients.

Publications

• Nuclear factor E2-related factor-2 has a differential impact on MCT1 and MCT4 lactate carrier expression in colonic epithelial cells: a condition favoring metabolic symbiosis between colorectal cancer and stromal cells. Oncogene, 37(1), 39-51.
  Diehl, K.; Dinges, L.-A.; Helm, O.; Ammar, N.; Plundrich, D.; Arlt, A.; Röcken, C.; Sebens, S. & Schäfer, H.
  
• Acute sedation-associated complications in GI endoscopy (ProSed 2 Study): results from the prospective multicentre electronic registry of sedation-associated complications. Gut, 68(3), 445-452.
  Behrens, Angelika; Kreuzmayr, Anton; Manner, Hendrik; Koop, Herbert; Lorenz, Albrecht; Schaefer, Claus; Plauth, Mathais; Jetschmann, Jens-Uwe; von Tirpitz, Christian; Ewald, Marcus; Sackmann, Michael; Renner, Wanja; Krüger, Martin; Schwab, Dieter; Hoffmann, Werner; Engelke, Olaf; Pech, Oliver; Kullmann, Frank; Pampuch, Sonja ... & Ell, Christian
  
• MTOR inhibitor-based combination therapies for pancreatic cancer. British Journal of Cancer, 118(3), 366-377.
  Hassan, Zonera; Schneeweis, Christian; Wirth, Matthias; Veltkamp, Christian; Dantes, Zahra; Feuerecker, Benedikt; Ceyhan, Güralp O.; Knauer, Shirley K.; Weichert, Wilko; Schmid, Roland M.; Stauber, Roland; Arlt, Alexander; Krämer, Oliver H.; Rad, Roland; Reichert, Maximilian; Saur, Dieter & Schneider, Günter
  
• Severe bleeding is a rare event in patients receiving lumen-apposing metal stents for the drainage of pancreatic fluid collections. Gut, 68(5), 945-946.
  Zeissig, Sebastian; Sulk, Stefan; Brueckner, Stefan; Matthes, Katja; Hohmann, Margarete; Reichel, Stephanie; Ellrichmann, Mark; Arlt, Alexander; Will, Uwe & Hampe, Jochen
  
• The antioxidant transcription factor Nrf2 modulates the stress response and phenotype of malignant as well as premalignant pancreatic ductal epithelial cells by inducing expression of the ATF3 splicing variant ΔZip2. Oncogene, 38(9), 1461-1476.
  Kha, My-Lan; Hesse, Lisa; Deisinger, Florian; Sipos, Bence; Röcken, Christoph; Arlt, Alexander; Sebens, Susanne; Helm, Ole & Schäfer, Heiner
  
• TRAIL/NF-κB/CX3CL1 Mediated Onco-Immuno Crosstalk Leading to TRAIL Resistance of Pancreatic Cancer Cell Lines. International Journal of Molecular Sciences, 19(6), 1661.
  Geismann, Claudia; Erhart, Wiebke; Grohmann, Frauke; Schreiber, Stefan; Schneider, Günter; Schäfer, Heiner & Arlt, Alexander
  
• Vedolizumab is associated with changes in innate rather than adaptive immunity in patients with inflammatory bowel disease. Gut, 68(1), 25-39.
  Zeissig, Sebastian; Rosati, Elisa; Dowds, C. Marie; Aden, Konrad; Bethge, Johannes; Schulte, Berenice; Pan, Wei Hung; Mishra, Neha; Zuhayra, Maaz; Marx, Marlies; Paulsen, Maren; Strigli, Anne; Conrad, Claudio; Schuldt, Dörthe; Sinha, Anupam; Ebsen, Henriette; Kornell, Sabin-Christin; Nikolaus, Susanna; Arlt, Alexander ... & Schreiber, Stefan
  
• Diagnostic and interventional digital pancreatoscopy as an “all-in-one” approach in chronic pancreatitis: a case report. Endoscopy, 51(10), E288-E289.
  Ellrichmann, Mark; Bethge, Johannes; Aselmann, Heiko; Becker, Thomas; Schreiber, Stefan & Arlt, Alexander
  
• Do We Really Need Another Special Issue on NF-κB in Cancer and Inflammation?. Cancers, 11(12), 1978.
  Geismann, Claudia & Arlt, Alexander
  
• EUS-guided drainage in the management of postoperative pancreatic leaks and fistulas (with video). Gastrointestinal Endoscopy, 89(2), 311-319.e1.
  Jürgensen, Christian; Distler, Marius; Arlt, Alexander; Brückner, Stefan; Ellrichmann, Mark; Matthes, Katja; Ludwig, Marleen; Sulk, Stephan; Romberg, Laura; Zeissig, Sebastian; Schafmayer, Clemens; Hinz, Sebastian; Welsch, Thilo; Bahra, Marcus; Aselmann, Heiko; Weitz, Jürgen; Klein, Fritz; Becker, Thomas & Hampe, Jochen
  
• NF-κB Dependent Chemokine Signaling in Pancreatic Cancer. Cancers, 11(10), 1445.
  Geismann, Claudia; Schäfer, Heiner; Gundlach, Jan-Paul; Hauser, Charlotte; Egberts, Jan-Hendrik; Schneider, Günter & Arlt, Alexander
  
• Coming in the Air: Hypoxia Meets Epigenetics in Pancreatic Cancer. Cells, 9(11), 2353.
  Geismann, Claudia & Arlt, Alexander
  
• Endoscopic ultrasound-guided drainage of pancreatic walled-off necrosis using 20-mm versus 15-mm lumen-apposing metal stents: an international, multicenter, case-matched study. Endoscopy, 52(03), 211-219.
  Parsa, Nasim; Nieto, Jose M.; Powers, Patrick; Mitsuhashi, Shuji; Abdelqader, Abdelhai; Hadzinakos, George; Anderloni, Andrea A.; Fugazza, Alessandro; James, Theodore W.; Arlt, Alexander; Ellrichmann, Mark; Aparicio, Jose Ramon; Trindade, Arvind J.; Stevens, Tyler K.; Chahal, Prabhleen; Shah, Shawn L.; Messallam, Ahmed A.; Lang, Gabriel; Fejleh, M. Phillip ... & Khashab, Mouen A.
  
• Impact of the Monocarboxylate Transporter-1 (MCT1)-Mediated Cellular Import of Lactate on Stemness Properties of Human Pancreatic Adenocarcinoma Cells. Cancers, 12(3), 581.
  Sandforth, Leontine; Ammar, Nourhane; Dinges, Lisa Antonia; Röcken, Christoph; Arlt, Alexander; Sebens, Susanne & Schäfer, Heiner
  
• Stem Cells and Organoid Technology in Precision Medicine in Inflammation: Are We There Yet?. Frontiers in Immunology, 11.
  Tran, Florian; Klein, Christine; Arlt, Alexander; Imm, Simon; Knappe, Evelyn; Simmons, Alison; Rosenstiel, Philip & Seibler, Philip
  
• The safety and efficacy of a new 20-mm lumen apposing metal stent (lams) for the endoscopic treatment of pancreatic and peripancreatic fluid collections: a large international, multicenter study. Surgical Endoscopy, 35(4), 1741-1748.
  Anderloni, Andrea; Fabbri, Carlo; Nieto, Jose; Uwe, Will; Dollhopf, Markus; Aparicio, José Ramón; Perez-Miranda, Manuel; Tarantino, Ilaria; Arlt, Alexander; Vleggaar, Frank; Vanbiervliet, Geoffrey; Hampe, Jochen; Kahaleh, Michel; Vila, Juan J.; Dayyeh, Barham K. Abu; Storm, Andrew C.; Fugazza, Alessandro; Binda, Cecilia; Charachon, Antoine ... & Kunda, Rastislav
  
• Get rid of pancreatic cancer by inhibiting garbage disposal?. Translational Oncology, 14(1), 100968.
  Geismann, Claudia & Arlt, Alexander
  
• Important role of Nfkb2 in the KrasG12D-driven carcinogenesis in the pancreas. Pancreatology, 21(5), 912-919.
  Hassan, Zonera; Schneeweis, Christian; Wirth, Matthias; Müller, Sebastian; Geismann, Claudia; Neuß, Thorsten; Steiger, Katja; Krämer, Oliver H.; Schmid, Roland M.; Rad, Roland; Arlt, Alexander; Reichert, Maximilian; Saur, Dieter & Schneider, Günter
  
• AP1/Fra1 confers resistance to MAPK cascade inhibition in pancreatic cancer. Cellular and Molecular Life Sciences, 80(1).
  Schneeweis, Christian; Diersch, Sandra; Hassan, Zonera; Krauß, Lukas; Schneider, Carolin; Lucarelli, Daniele; Falcomatà, Chiara; Steiger, Katja; Öllinger, Rupert; Krämer, Oliver H.; Arlt, Alexander; Grade, Marian; Schmidt-Supprian, Marc; Hessmann, Elisabeth; Wirth, Matthias; Rad, Roland; Reichert, Maximilian; Saur, Dieter & Schneider, Günter
  
• Endoscopic Management of Anastomotic Leakage after Esophageal Surgery: Ten Year Analysis in a Tertiary University Center. Clinical Endoscopy, 55(1), 58-66.
  El-Sourani, Nader; Miftode, Sorin; Bockhorn, Maximilian; Arlt, Alexander & Meinhardt, Christian
  
• Incidence of ablation‐induced esophageal lesions and gastroparesis in patients undergoing ablation index guided high power short duration atrial fibrillation ablation. Journal of Cardiovascular Electrophysiology, 34(1), 82-89.
  List, Stephan; Meinhardt, Christian; Mueller, Julian; Deneke, Thomas; Barth, Sebastian; Waechter, Christian; Luesebrink, Ulrich; Elsaesser, Albrecht; Arlt, Alexander & Halbfass, Philipp
  
• Role of Epithelial-to-Mesenchymal Transition for the Generation of Circulating Tumors Cells and Cancer Cell Dissemination. Cancers, 14(22), 5483.
  Noubissi, Nzeteu Gaetan Aime; Geismann, Claudia; Arlt, Alexander; Hoogwater, Frederik J. H.; Nijkamp, Maarten W.; Meyer, N. Helge & Bockhorn, Maximilian
  
• The HSF1-CPT1a Pathway Is Differentially Regulated in NAFLD Progression. Cells, 11(21), 3504.
  Breternitz, Wiebke; Sandkühler, Friedrich; Grohmann, Frauke; Hampe, Jochen; Brosch, Mario; Herrmann, Alexander; Schafmayer, Clemens; Meinhardt, Christian; Schreiber, Stefan; Arlt, Alexander & Geismann, Claudia
  
• High prevalence of incidental endoscopic findings at routine endoscopy after atrial fibrillation ablation: Do we need a screening endoscopy for the upper gastrointestinal tract in the general population?. European Journal of Internal Medicine, 111, 54-62.
  Meinhardt, Christian; List, Stephan; Chamieh, Alexander Elias; Fehrendt, Hinrich; Meves, Volker; Mohamed, Moustafa; Müller, Julian; Deneke, Thomas; Geismann, Claudia; Elsässer, Albrecht; Arlt, Alexander & Halbfass, Philipp
  
• NF-κB/RelA controlled A20 limits TRAIL-induced apoptosis in pancreatic cancer. Cell Death & Disease, 14(1).
  Geismann, Claudia; Hauser, Charlotte; Grohmann, Frauke; Schneeweis, Christian; Bölter, Nico; Gundlach, Jan-Paul; Schneider, Günter; Röcken, Christoph; Meinhardt, Christian; Schäfer, Heiner; Schreiber, Stefan & Arlt, Alexander