title: Antagonizing Integrin β3 Increases Immunosuppression in Cancer.
abstract: Integrin β3 is critical for tumor invasion, neoangiogenesis, and inflammation, making it a promising cancer target. However, preclinical and clinical data of integrin β3 antagonists have demonstrated no benefit or worse outcomes. We hypothesized that integrin β3 could affect tumor immunity and evaluated tumors in mice with deletion of integrin β3 in macrophage lineage cells (β3KOM). β3KOM mice had increased melanoma and breast cancer growth with increased tumor-promoting M2 macrophages and decreased CD8(+) T cells. Integrin β3 antagonist, cilengitide, also enhanced tumor growth and increased M2 function. We uncovered a negative feedback loop in M2 myeloid cells, wherein integrin β3 signaling favored STAT1 activation, an M1-polarizing signal, and suppressed M2-polarizing STAT6 activation. Finally, disruption of CD8(+) T cells, macrophages, or macrophage integrin β3 signaling blocked the tumor-promoting effects of integrin β3 antagonism. These results suggest that effects of integrin β3 therapies on immune cells should be considered to improve outcomes. Cancer Res; 76(12); 3484-95. ©2016 AACR.
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Xinming
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Alison K
authors.initials: AK
authors.lastname: Esser
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Amend
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Yalin
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Ross
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Fox
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
authors.forename: Veronica
authors.initials: V
authors.lastname: Steri
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Roomp
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fontana
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Hurchla
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Brett L
authors.initials: BL
authors.lastname: Knolhoff
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Meyer
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Morgan
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Julia C
authors.initials: JC
authors.lastname: Tomasson
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Novack
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri. Deparment of Medicine, Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
authors.affiliation: Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Roberta
authors.initials: R
authors.lastname: Faccio
authors.affiliation: Deparment of Medicine, Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Deborah V
authors.initials: DV
authors.lastname: Novack
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Robinson
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri. Deparment of Medicine, Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Teitelbaum
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: David G
authors.initials: DG
authors.lastname: DeNardo
authors.affiliation: Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg. Department of Internal Medicine II, Saarland University Medical Center, Homburg/Saar, Germany.
authors.forename: Jochen G
authors.initials: JG
authors.lastname: Schneider
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri. KWEILBAE@DOM.wustl.edu.
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Weilbaecher
mesh_terms: D000818:Animals; D007108:Immune Tolerance; D039661:Integrin beta3 / Q000502:physiology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000502:physiology; D050800:STAT6 Transcription Factor / Q000502:physiology; D000072377:Syk Kinase / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D039661:Integrin beta3; D050794:STAT1 Transcription Factor; D050800:STAT6 Transcription Factor; C494080:Stat1 protein, mouse; C494100:Stat6 protein, mouse; D000072377:Syk Kinase; C000606897:Syk protein, mouse