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PMID: 23897983 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

The Journal of experimental medicine ·Vol. 210 ·No. 9 ·2013-08-26 ·Pages 1711-28

Raccosta L, Fontana R, Maggioni D, Lanterna C, Villablanca EJ, Paniccia A, Musumeci A, Chiricozzi E, Trincavelli ML, Daniele S, Martini C, Gustafsson JA, Doglioni C, Feo SG, Leiva A, Ciampa MG, Mauri L, Sensi C, Prinetti A, Eberini I, Mora JR, Bordignon C, Steffensen KR, Sonnino S, Sozzani S, Traversari C, Russo V

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.

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 Therapy Ligands Liver X Receptors Mass Spectrometry Mice Myeloid Cells/metabolism,pathology Neoplasms/blood supply,metabolism,pathology Neovascularization, Pathologic/metabolism,pathology Neutrophils/metabolism Orphan Nuclear Receptors/metabolism Receptors, G-Protein-Coupled/metabolism Receptors, Interleukin-8B/metabolism Signal Transduction Sterols/metabolism
Chemicals
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
Authors & Affiliations
27 authors, click to expand affiliations / ORCID
Raccosta Laura
Cancer Gene Therapy Unit, Program of Immunology and Bio Immuno Gene Therapy of Cancer, Division of Molecular Oncology, Scientific Institute San Raffaele, Milan, Italy.
Fontana Raffaella
Maggioni Daniela
Lanterna Claudia
Villablanca Eduardo J
Paniccia Aida
Musumeci Andrea
Chiricozzi Elena
Trincavelli Maria Letizia
Daniele Simona
Martini Claudia
Gustafsson Jan-Ake
Doglioni Claudio
Feo Safiyè Gonzalvo
Leiva Andrea
Ciampa Maria Grazia
Mauri Laura
Sensi Cristina
Prinetti Alessandro
Eberini Ivano
Mora J Rodrigo
Bordignon Claudio
Steffensen Knut R
Sonnino Sandro
Sozzani Silvano
Traversari Catia
Russo Vincenzo
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20130440
Published
2013-08-26
Epub
2013-00-29
Pages
1711-28
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC3754872
Subset
IM
Grants
Worldwide Cancer Research · 11-0751 · United Kingdom
NCCDPHP CDC HHS · DP2 2009A054301 · United States
External Links
PubMed source DOI: 10.1084/jem.20130440 PMC Full Text View journal details
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