Endogenous DEL-1 restrains melanoma lung metastasis by limiting myeloid cell-associated lung inflammation

Distant metastasis represents the primary cause of cancer-associated death. Pulmonary metastasis is most frequently seen in many cancers, largely driven by lung inflammation. Components from primary tumor or recruited leukocytes are known to facilitate metastasis formation. However, contribution of target site-specific host factor to metastasis is poorly understood. Here, we show that developmental endothelial locus-1 (DEL-1), an anti-inflammatory factor abundant in the lung and down-regulated by inflammatory insults, protects from melanoma lung metastasis independently of primary tumor development and systemic immunosurveillance. DEL-1 deficiency is associated with gene profiles that favor metastatic progression with inflammation and defective immunosurveillance. Mechanistically, DEL-1 deficiency primarily influences Ly6G⁺ neutrophil accumulation in lung metastatic niche, leading to IL-17A up-regulation from γδ T cells and reduced antimetastatic NK cells. In support, neutrophil depletion or recombinant DEL-1 treatment profoundly reverses these effects. Thus, our results identify DEL-1 as a previously unrecognized link between tumor-induced inflammation and pulmonary metastasis.