The oxysterol-CXCR2 axis plays a key role in the recruitment of tumor-promoting neutrophils

J Exp Med. 2013 Aug 26;210(9):1711-28. doi: 10.1084/jem.20130440. Epub 2013 Jul 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / metabolism
  • CD11b Antigen / metabolism
  • Cell Proliferation
  • Chemotaxis
  • Chromatography, High Pressure Liquid
  • Disease Models, Animal
  • HEK293 Cells
  • Humans
  • Hydroxycholesterols / metabolism
  • Immunosuppression
  • Ligands
  • Liver X Receptors
  • Mass Spectrometry
  • Mice
  • Myeloid Cells / metabolism
  • Myeloid Cells / pathology
  • Neoplasms / blood supply
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Neutrophils / metabolism*
  • Orphan Nuclear Receptors / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Interleukin-8B / metabolism*
  • Signal Transduction*
  • Sterols / metabolism*

Substances

  • Antigens, Ly
  • CD11b Antigen
  • Hydroxycholesterols
  • Ligands
  • Liver X Receptors
  • Ly6G antigen, mouse
  • Orphan Nuclear Receptors
  • Receptors, G-Protein-Coupled
  • Receptors, Interleukin-8B
  • Sterols
  • 22-hydroxycholesterol