Group 3 innate lymphoid cell regulation of vascular remodeling at homeostasis and in cancer

Principle Investigator

Scientific interest within the context of the graduate college

We are interested in understanding the mechanisms by which a specific subset of innate lymphocytes, namely group 3 innate lymphoid cells (ILC3), regulate immune responses and tissue functions at homeostasis and in cancer. ILC3 are tissue-resident cells located at barrier tissues which occupy specific tissue niches where they constantly produce cytokines, particularly IL-22. ILC3-derived IL-22 maintains the integrity of epithelial surfaces and regulates cell processes involved in epithelial cell malignant transformation. However, the role of ILC3 and IL-22 in vascular remodeling and angiogenesis, which is a key step in tumorigenesis and a hallmark of cancer, remains largely unexplored. We seek to systematically investigate the role of ILC3 in the regulation of endothelial cell development and function in homeostasis and during tumor evolution to identify new therapeutic targets.

Project description

ILC3 are tissue-resident IL-22-producing cells that play an important role in the adaptation of tissues to environmental changes and stressors.¹ IL-22 is a cytokine belonging to the IL-10 family that exerts regulatory functions by binding to its receptor IL-22RA1, selectively expressed by non-hematopoietic cells.² Unpublished work from our laboratory recently showed that IL-22 regulates melanoma angiogenesis by inducing molecular programs in tumor endothelial cells that promote the formation of aberrant, dysfunctional and leaky tumor vessels. This argues for potential ILC3-endothelial cell pathways regulating the formation of new vessels at barrier tissues that can be co-opted by the tumor “neo-organ”. Blood vessels are crucial to gut function and pervade all intestinal tissue layers.³ The gut vascular barrier (GVB) is composed of closely interacting endothelial cells that display unique features.^3,4 Alteration of the GVB due to pathological tissue remodeling leads to the leakage of the gut and the development of intestinal and extraintestinal diseases.^2,4 A better understanding of the ILC3-dependent regulation of endothelial cell differentiation and of their function in the intestine could lead to the identification of an ILC3-endothelial cell module regulating intestinal homeostasis and tumor progression, promoting the development of novel therapeutic approaches to treat cancer.^5,6

Aim 1: To investigate ILC3 regulation of intestinal endothelial cell development and function. The small intestine is a very plastic organ which undergoes postnatal dynamic changes.⁷ Our preliminary results suggest that IL-22 has a role in the regulation of physiological postnatal vascular remodeling. Genetically modified mouse models will be used to explore the molecular mechanisms by which ILC3 and IL-22 contribute to intestinal vasculogenesis from early to adult mouse life. Molecular (qPCR, RNA-sequencing) and cell biology (flow cytometry, immunofluorescence) approaches will be employed. In vivo functional vascular assays will be also applied.

Aim 2: To investigate ILC3 regulation of angiogenesis in intestinal cancer. After the identification of ILC3 and IL-22-dependent pathways regulating physiological vascular remodeling, we will establish preclinical models of intestinal cancer, either inflammation-induced or oncogene-induced. Mouse surgery and histopathological analysis, as well as molecular and cellular biology techniques will be used to investigate the role of the ILC3-endothelial cell module in cancer onset and progression.

Application details

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