Eosinophils and Bioactive Lipid Mediators Regulate Skin Inflammation and Cancer Growth

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer, with local immunity playing a key role in regulating outcome. Nonresolving inflammation has been suggested to drive cancer growth; however, a fundamental understanding of the tumor immune microenvironment in cSCC is still lacking. In this study, we demonstrate tissue-associated tumor eosinophilia in both human and murine cSCC and show that eosinophils promote epithelial hyperplasia and tumor outgrowth. The skin eosinophils display tissue adaptation and dynamically alter their transcriptome according to the microenvironment. Furthermore, we show that the skin bioactive lipidome is significantly altered during inflammation and in cSCC and that this is regulated by eosinophils. Inflamed skin and cSCC tissue are dominated by lipid mediators synthesized by lipoxygenase enzymes, and our results suggest that eosinophils influence the balance between proinflammatory and proresolving lipid mediators. We demonstrate that lipid mediators can regulate epithelial cell expansion, with PCTR1 reducing inflammation-driven growth of tumor cells and eosinophil-driven eoxin C4 blocking this effect. Together, these findings highlight that eosinophils and specific bioactive lipid mediators play important roles in skin biology and carcinogenesis and point to potential previously unreported strategies for treatment of inflammatory disorders and epithelial malignancies.