NR4A1 (Nur77) dependent monocytes patrol the lung vasculature and inhibit tumor cell invasion (P5068)

Abstract

Abstract The nuclear receptor NR4A1 (Nur77) is expressed in monocytes and macrophages, yet its function in regulating inflammation associated with cancer is uncertain. Our previous studies identified that Nur77 regulates the development of patrolling Ly6C- monocytes and is involved in the resolution of inflammation. In the current study, we sought to determine how absence of Nur77 in hematopoietic cells impacts tumor growth and metastasis. Mice deficient in Nur77 showed a significant increase in growth and lung metastasis of syngeneic B16F10 melanoma. Increased tumor seeding of the lung was visible after only 4 days post IV tumor transfer, and appears to be specific to the lung. In vivo imaging reveals that Nur77-defficient mice have a drastic reduction in cells patrolling the lung vasculature, and that these patrolling monocytes establish early immune interactions with tumor cells and granulocytes in the lung. Furthermore, over-expression of Nur77 in human monocytes inhibited angiogenesis and invasion of human tumor cells in co-culture assays. We conclude that the absence of Nur77-regulated patrolling monocytes in combination with polarization of myeloid cells towards a pro-inflammatory and pro-angiogenic phenotype contributes to early tumor cell invasion of the vasculature and growth in the lung. These studies indicate that Nur77 is a novel target for modulating the inflammatory phenotype of monocytes and macrophages in inflammatory diseases, including cancers.