title: Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy.
abstract: Tumor-infiltrating myeloid cells (TIMs) support tumor growth by promoting angiogenesis and suppressing antitumor immune responses. CSF-1 receptor (CSF1R) signaling is important for the recruitment of CD11b(+)F4/80(+) tumor-associated macrophages (TAMs) and contributes to myeloid cell-mediated angiogenesis. However, the impact of the CSF1R signaling pathway on other TIM subsets, including CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs), is unknown. Tumor-infiltrating MDSCs have also been shown to contribute to tumor angiogenesis and have recently been implicated in tumor resistance to antiangiogenic therapy, yet their precise involvement in these processes is not well understood. Here, we use the selective pharmacologic inhibitor of CSF1R signaling, GW2580, to demonstrate that CSF-1 regulates the tumor recruitment of CD11b(+)Gr-1(lo)Ly6C(hi) mononuclear MDSCs. Targeting these TIM subsets inhibits tumor angiogenesis associated with reduced expression of proangiogenic and immunosuppressive genes. Combination therapy using GW2580 with an anti-VEGFR-2 antibody synergistically suppresses tumor growth and severely impairs tumor angiogenesis along with reverting at least one TIM-mediated antiangiogenic compensatory mechanism involving MMP-9. These data highlight the importance of CSF1R signaling in the recruitment and function of distinct TIM subsets, including MDSCs, and validate the benefits of targeting CSF1R signaling in combination with antiangiogenic drugs for the treatment of solid cancers.
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Saul J
authors.initials: SJ
authors.lastname: Priceman
authors.forename: James L
authors.initials: JL
authors.lastname: Sung
authors.forename: Zory
authors.initials: Z
authors.lastname: Shaposhnik
authors.forename: Jeremy B
authors.initials: JB
authors.lastname: Burton
authors.forename: Antoni X
authors.initials: AX
authors.lastname: Torres-Collado
authors.forename: Diana L
authors.initials: DL
authors.lastname: Moughon
authors.forename: Mai
authors.initials: M
authors.lastname: Johnson
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.forename: Donald A
authors.initials: DA
authors.lastname: Cohen
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Iruela-Arispe
authors.forename: Lily
authors.initials: L
authors.lastname: Wu
mesh_terms: D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008264:Macrophages / Q000166:cytology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000473:pathology; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy / Q000473:pathology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: C506269:5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine; D000840:Anisoles; D011743:Pyrimidines; D016186:Receptor, Macrophage Colony-Stimulating Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; D020780:Matrix Metalloproteinase 9