title: G-CSF regulates macrophage phenotype and associates with poor overall survival in human triple-negative breast cancer.
abstract: Tumor-associated macrophages (TAMs) have been implicated in the promotion of breast cancer growth and metastasis, and a strong infiltration by TAMs has been associated with estrogen receptor (ER)-negative tumors and poor prognosis. However, the molecular mechanisms behind these observations are unclear. We investigated macrophage activation in response to co-culture with several breast cancer cell lines (T47D, MCF-7, BT-474, SKBR-3, Cal-51 and MDA-MB-231) and found that high granulocyte colony-stimulating factor (G-CSF) secretion by the triple-negative breast cancer (TNBC) cell line MDA-MB-231 gave rise to immunosuppressive HLA-DRlomacrophages that promoted migration of breast cancer cells via secretion of TGF-α. In human breast cancer samples (n = 548), G-CSF was highly expressed in TNBC (p< 0.001) and associated with CD163+macrophages (p< 0.0001), poorer overall survival (OS) (p= 0.021) and significantly increased numbers of TGF-α+cells. While G-CSF blockade in the 4T1 mammary tumor model promoted maturation of MHCIIhiblood monocytes and TAMs and significantly reduced lung metastasis, anti-CSF-1R treatment promoted MHCIIloF4/80hiMRhianti-inflammatory TAMs and enhanced lung metastasis in the presence of high G-CSF levels. Combined anti-G-CSF and anti-CSF-1R therapy significantly increased lymph node metastases, possibly via depletion of the so-called "gate-keeper" subcapsular sinus macrophages. These results indicate that G-CSF promotes the anti-inflammatory phenotype of tumor-induced macrophages when CSF-1R is inhibited and therefore caution against the use of M-CSF/CSF-1R targeting agents in tumors with high G-CSF expression.
authors.affiliation: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zürich , Zurich, Switzerland.
authors.forename: Maija
authors.initials: M
authors.lastname: Hollmén
authors.affiliation: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zürich , Zurich, Switzerland.
authors.forename: Sinem
authors.initials: S
authors.lastname: Karaman
authors.affiliation: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zürich , Zurich, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Schwager
authors.affiliation: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zürich , Zurich, Switzerland.
authors.forename: Angela
authors.initials: A
authors.lastname: Lisibach
authors.affiliation: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zürich , Zurich, Switzerland.
authors.forename: Ailsa J
authors.initials: AJ
authors.lastname: Christiansen
authors.affiliation: Medicity Research Laboratory, University of Turku , Turku, Finland.
authors.forename: Mikael
authors.initials: M
authors.lastname: Maksimow
authors.affiliation: Institute of Surgical Pathology, University Hospital Zürich , Zurich, Switzerland.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Varga
authors.affiliation: Medicity Research Laboratory, University of Turku , Turku, Finland.
authors.forename: Sirpa
authors.initials: S
authors.lastname: Jalkanen
authors.affiliation: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zürich , Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Detmar
keywords: CSF3; HLA-DR; M-CSF; TGF-α; TNBC; tumor-associated macrophages