Deciphering type 2 innate lymphoid cell/epithelial progenitor cell crosstalk in pancreas regeneration and neoplasia

Projektinformationen

PanILC

ID Finanzhilfevereinbarung: 840501

DOI

10.3030/840501

Projekt abgeschlossen

EK-Unterschriftsdatum 15 April 2019

Startdatum 1 Juli 2019

Enddatum 30 Juni 2021

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 224 933,76

EU-Beitrag

€ 224 933,76

Koordiniert durch

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
United Kingdom

Periodic Reporting for period 1 - PanILC (Deciphering type 2 innate lymphoid cell/epithelial progenitor cell crosstalk in pancreas regeneration and neoplasia)

Berichtszeitraum: 2019-07-01 bis 2021-06-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Over the last decade, treatment of cancer has been revolutionised by the tremendous success of cancer immunotherapies, i.e. drugs aiming at boosting the patient’s own immune system against its tumour. Such treatments have led to improved survival and long-term remission in a substantial proportion of treated patients, and have now become the standard of care in specific tumour types, such as melanoma. However, not all types of tumours are sensitive to immunotherapies. One such example is pancreatic cancer, among which pancreatic adenocarcinoma (PDAC) represents the most common subtype.
PDAC is one of the most aggressive cancer types, with a five-year survival rate of less than 5%. Among PDAC risk factors, pancreatitis emerges as a critical player in tumour development, as evidenced from both human data and pre-clinical mouse models. Despite intensive research, no improvement in this five-year survival rate has been achieved over the past 4 decades, illustrating how cutting-edge research in this field is crucial to tackle such an unmet clinical need.
An extensive amount of work has been achieved at defining critical signalling pathways for pancreatic cancer cell survival as well as the mutational landscape in pancreatic tumours. However, our understanding of the interaction between immune cells and the exocrine pancreas – healthy, inflamed or tumoral – has just begun to be explored.
In this work we set out to test the hypothesis that a novel subset of tissue-resident immune cells termed “type-2 innate lymphoid cells”, or ILC2s, influence the epithelial cell niche in the pancreas by locally regulating inflammation. Using state-of-the art mouse models of pancreatitis and pancreatic tumors, our results reveal distinct and previously unappreciated roles for ILC2s-driven mechanisms in regulating pancreatic epithelial cells upon inflammation and tumorigenesis.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

In the first part of this research project, we have characterised tissue-resident populations of ILC2s in the mouse healthy pancreas using cutting-edge approaches. We have addressed the functional role of these cells in pancreatic inflammation using a mouse model of acute pancreatitis induced by the intraperitoneal injection of the cholecystokinin analogue caerulein. We found out that ILC2s are early cellular effectors of the damage response occurring in this model, which translates into the destruction of the exocrine pancreas parenchyma. On the other hand, we showed that later in disease ILC2 may contribute to the regeneration of the pancreas by interacting with other immune cells called regulatory T cells (Tregs).

In the second part of the project, we have used an orthotopic mouse model of pancreatic ductal adenocarcinoma (PDAC) to address the role played by ILC2s in pancreas carcinogenesis. We demonstrated that mice deficient ILC2s show reduced tumour growth and increased survival, suggesting that ILC2s may support disease progression. Interestingly, ILC2-deficient tumour-bearing mice show a shift towards increased anti-tumour immune cells. Thus, we propose that in pancreatic tumour development, ILC2s impedes an efficient anti-tumour immune response.

Altogether, we have identified novel and distinct role for ILC2s during pancreatitis, and investigated their role in PDAC development. These results will be disseminated shortly via publication in peer-reviewed scientific journals.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Pancreatic cancer is an unmet clinical need. Much hope has been brought lately for the use of immunotherapy as a therapeutic option, but with little success so far. Our project devoted to the study of tissue-resident ILC2s and Tregs in pancreas regeneration as well as tumour development addressed gaps in knowledge in this area. Indeed, whilst the role of Tregs in tumour progression is well established, whether an ILC2-Treg axis could play a role during tumour-promoting inflammation or tumour development had not been studied, and our results suggest that targeting ILC2s could potentially be a novel therapeutic option for pancreatic cancer. In addition, our results also reveal previously unappreciated role for ILC2s and Tregs in the biology of the exocrine pancreas, which had been largely ignored thus far. Thus, our results reveal fundamental mechanism of disease and will help the discovery and design of new therapeutic targets. Finally, our results will guide the understanding of potential side effects of strategies aiming at the modulation of Treg numbers/function, which are widely explored nowadays in the era of cancer immunotherapy, but also for type-1 diabetes.

Graphical Abstract