The role of eosinophils in skin inflammation and carcinogenesis

Abstract

Cutaneous squamous cell carcinoma (cSCC) is one of the most common human cancers. cSCC is often associated with immune dysfunction and skin inflammation plays a prominent role in carcinogenesis. Eosinophils are effector immune cells which have been observed in several human cancers and are associated with tissue inflammation. Here, I explore the role of eosinophils in skin inflammation and cSCC development using murine models. I found that eosinophils were present in both healthy and inflamed skin and accumulated inside cSCC. I demonstrated that skin eosinophilia was dependent on CCR3 and that epidermal hyperplasia, which is a hallmark of skin inflammation, was significantly reduced in mice lacking eosinophils (ΔdblGATA) compared to wildtype (WT) mice. Using an inflammation-driven model of cSCC, I demonstrated that ΔdblGATA mice were significantly less susceptible to carcinogenesis, with delayed onset and overall, less tumour development. To investigate possible mechanisms by which eosinophils could affect skin health, I analysed the bioactive lipidome in healthy, inflamed and tumour skin tissue of WT and ΔdblGATA mice. I found significant alterations in the expression of bioactive lipid mediators between different tissue states in both WT and ΔdblGATA skin and demonstrated that the bioactive lipid mediator profile was significantly regulated by eosinophils. I selected two eosinophil-driven lipid mediators; the pro-resolving mediator protein conjugates in tissue regeneration 1 (PCTR1) and the eosinophil specific mediator Eoxin C4. Topical application of PCTR1 and Eoxin C4 regulated the tissue response to inflammation and reduced tumour growth in WT mice. Tissue eosinophils were further characterised by TempO-seq RNA transcript analysis which showed distinct profiles of skin eosinophils compared to bone marrow and spleen eosinophils. The eosinophil transcriptome was also altered in tumour compared to healthy or inflamed skin. In conclusion, my data suggests a prominent role for skin eosinophils in driving epithelial cell proliferation and tumour outgrowth.