Exploring the role of macrophage-niche crosstalk in radiation-induced salivary gland degeneration

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Radiotherapy is a life-saving treatment for those with head and neck cancer. Although radiotherapy is very often successful in treating the cancer, a serious side-effect is damage to healthy tissue near the tumour(s), including the salivary glands. This tissue damage results in a reduced ability to produce saliva (a condition known as chronic dry mouth or xerostomia), which leads to difficulties with eating, speaking and sleeping and a risk of choking. Furthermore, it causes tooth decay and oral health problems. Thus, the side-effects of radiotherapy adversely affect a patient's quality of life. Existing treatments for chronic dry mouth (e.g. saliva substitutes and mouthwashes) only give short-term relief and therefore there is a need to develop better, more effective treatments. The salivary glands degenerate over time following radiotherapy. However, why this happens is currently unknown. In this proposal we will first extensively profile what happens in the salivary gland after radiotherapy, using glands isolated from both mice and humans. We already know that macrophages, a cell that has long been considered a key player in the repair and regeneration of many different organs, are essential for salivary gland regeneration after radiotherapy, and in their absence efficient regeneration does not occur. Conversely, over time macrophages are lost after radiotherapy, suggesting that something that supports the macrophages is missing. We know that salivary gland macrophages rely on a factor called Colony-Stimulating-Factor-1 (CSF1) and that CSF1 declines after radiotherapy, but we do not know which cells in the salivary gland produce CSF1. Here we will use genetically altered mice to deplete CSF1 in specific cells and explore the effect on macrophages. Finally, we will assess if we can rescue salivary gland function after radiotherapy by treating with CSF1 or by transplanting new macrophages into the salivary glands. Collectively, this will tell us which cells we should be focussing on to get better regeneration and whether we can ultimately rescue radiotherapy injury.