Exploring Neuro-immune Networks in Cancer: Focus on Macrophages

Cortese, Nina (2019). Exploring Neuro-immune Networks in Cancer: Focus on Macrophages. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f4f0


This thesis is composed of two parts; the first one summarizes results of two ancillary projects I was involved in, which have been fundamental to provide the ground to my PhD project. The first project (“TAM-CTX Project”) concerns the interaction of tumour-associated macrophages with chemotherapy in pancreatic cancer. The second project (“BAT Project”) was carried out in the laboratory of Prof. Steffen Jung, at the Weizmann Institute in Rehovot, and contributed to the definition of the important role of macrophages in the control of tissue innervation. The main part of the thesis includes the results of my PhD project (“Neuro-immune Project”) and is focused on the analysis of neuro-immune networks in cancer. The central nervous system reflexively regulates the inflammatory response, via a direct modulation of immune cells by peripheral nerves. In the context of cancer this phenomenon is still largely unexplored. Macrophages hold a key position in neural-mediated circuits. To define whether a neural control of macrophage functions in tumours exists, we have investigated the macrophage-neural interaction in a preclinical model of colorectal cancer (AOM/DSS). Firstly, we characterized by confocal microscopy the major components (neurons and Enteric Nervous System (ENS)-associated glia) of the neural networks in the gastrointestinal wall, peculiarly organized in each layer. We have visualized the spatial interaction of the complex intestinal neural networks with macrophages. F4/80+ macrophages were found in closed proximity to nerve fibers throughout the intestinal wall. We found a closer association of macrophages to nerves in tumor bearing mice. We hypothesized that this could be due to a neural remodelling process, and in fact tumour-bearing mice showed a significantly higher number of Nestin+ cells, possibly suggesting the recruitment of neural progenitor cells. Moreover, macrophages isolated from AOM/DSS treated mice up-regulated a neuro-modulatory profile, and in particular we found an increased expression in Neuregulin 1, a protein with pivotal role in the nervous and cardiovascular systems. The increased expression of Neuregulin 1 in colonic macrophages of tumour-bearing mice was further confirmed by immunofluorescence on tissue and single cell RNA-sequencing. Overall, these results intimate a modification of neural-macrophage networks in colorectal cancer that could be important in the regulation of macrophage function in tumours.

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