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

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

Objective

Regulation of the epithelial stem cell compartment is critical for tissue homeostasis and regeneration. Consequently, imbalance in this process, through acquisition of somatic mutations for instance, may give rise to tumorigenesis. Emerging reports reveal that regulatory T cells (Tregs) can modulate epithelial stem cell dynamics in the skin, while type 2 innate lymphoid cells (ILC2s) are known to influence tissue-regeneration. Recent work in our laboratory has elucidated that ILC2s crosstalk is essential for local Tregs expansion. We hypothesize that tissue-resident ILC2s influence the stem cell niche by recruiting and regulating Tregs, and that such a mechanism could be key to tissue regeneration as well as tumor development.
Preliminary data in the lab suggest that the intraperitoneal injection of the potent ILC2 inducer IL-33 in mice activates ILC2 in the pancreas, and that a concomitant increase in Treg numbers is observed in this organ. This raises the possibility of the existence of a crosstalk between ILC2s and Tregs in the pancreas upon inflammation, such as in the case of pancreatitis. Given the considerable attention brought lately on the ability of Tregs to develop tissue-promoting capacities, we postulate that regeneration of the exocrine pancreas following pancreatitis may be driven by such pancreatic Tregs upon their “priming” by ILC2.
The present project will therefore focus on understanding the role of ILC2 and Tregs and their possible crosstalk in pancreatitis development, as well as in the regeneration process that follows, i.e. the interaction of these immune cells with epithelial progenitors. As pancreatitis is a major risk factor for the development of pancreatic cancer, the resulting observations will then be extended to the analysis of the role of ILC2/Treg crosstalk in tumor development in an orthotopic mouse model of pancreatic tumours as well as in a genetic mouse model of pancreatic adenocarcinoma.
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Coordinator

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE

Address

Trinity Lane The Old Schools
Cb2 1tn Cambridge

United Kingdom

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 224 933,76

Project information

Grant agreement ID: 840501

Status

Grant agreement signed

  • Start date

    1 July 2019

  • End date

    30 June 2021

Funded under:

H2020-EU.1.3.2.

  • Overall budget:

    € 224 933,76

  • EU contribution

    € 224 933,76

Coordinated by:

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE

United Kingdom