ABSTRACT
Tumor-infiltrating immune cells can be conditioned by molecules released within the microenvironment to thwart antitumor immune responses, thereby facilitating tumor growth. Among immune cells, neutrophils play an important protumorigenic role by favoring neoangiogenesis and/or by suppressing antitumor immune responses. Tumor-derived oxysterols have recently been shown to favor tumor growth by inhibiting dendritic cell migration toward lymphoid organs. We report that tumor-derived oxysterols recruit protumor neutrophils in a liver X receptor (LXR)-independent, CXCR2-dependent manner, thus favoring tumor growth by promoting neoangiogenesis and immunosuppression. We demonstrate that interfering with the oxysterol-CXCR2 axis delays tumor growth and prolongs the overall survival of tumor-bearing mice. These results identify an unanticipated protumor function of the oxysterol-CXCR2 axis and a possible target for cancer therapy.
Subject(s)
Neoplasms/metabolism , Neutrophils/metabolism , Receptors, Interleukin-8B/metabolism , Signal Transduction , Sterols/metabolism , Animals , Antigens, Ly/metabolism , CD11b Antigen/metabolism , Cell Proliferation , Chemotaxis , Chromatography, High Pressure Liquid , Disease Models, Animal , HEK293 Cells , Humans , Hydroxycholesterols/metabolism , Immunosuppression Therapy , Ligands , Liver X Receptors , Mass Spectrometry , Mice , Myeloid Cells/metabolism , Myeloid Cells/pathology , Neoplasms/blood supply , Neoplasms/pathology , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Orphan Nuclear Receptors/metabolism , Receptors, G-Protein-Coupled/metabolismABSTRACT
Tuning is a key aspect of inflammatory reaction essential in homeostasis and pathology. An emerging mechanism for negative regulation of proinflammatory cytokines is based on non-signaling IL-1/TLR receptors and chemokine receptors competing with signaling receptors for ligand binding and sustaining ligand internalization and degradation. Biological activities of IL-1R/TLR receptors are under control of membrane-bound binding molecules lacking the signaling domain, soluble receptor antagonists, and intracellular signaling inhibitors. The chemokine system includes at least three 'silent' receptors with distinct specificity and tissue distribution. D6 is the best characterized representative member of this class of negative regulators, binds most inflammatory, but not homeostatic, CC chemokines and shuttles in a ligand-independent way from the plasma membrane to endocytic compartments where chemokines are targeted to degradation. In vitro and in vivo evidence, including results with gene targeted mice, is consistent with the view that these non-signaling receptors for proinflammatory cytokines possess unique functional and structural features which make them ideally adapted to act as a decoy and scavenger receptors, with a non redundant role in dampening tissue inflammation and tuning draining lymph nodes reactivity.
