title: B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma.
abstract: Tumor-associated macrophages are a prominent component of ovarian cancer stroma and contribute to tumor progression. B7-H4 is a recently identified B7 family molecule. We show that primary ovarian tumor cells express intracellular B7-H4, whereas a fraction of tumor macrophages expresses surface B7-H4. B7-H4+ tumor macrophages, but not primary ovarian tumor cells, suppress tumor-associated antigen-specific T cell immunity. Blocking B7-H4-, but not arginase-, inducible nitric oxide synthase or B7-H1 restored the T cell stimulating capacity of the macrophages and contributes to tumor regression in vivo. Interleukin (IL)-6 and IL-10 are found in high concentrations in the tumor microenvironment. These cytokines stimulate macrophage B7-H4 expression. In contrast, granulocyte/macrophage colony-stimulating factor and IL-4, which are limited in the tumor microenvironment, inhibit B7-H4 expression. Ectopic expression of B7-H4 makes normal macrophages suppressive. Thus, B7-H4+ tumor macrophages constitute a novel suppressor cell population in ovarian cancer. B7-H4 expression represents a critical checkpoint in determining host responses to dysfunctional cytokines in ovarian cancer. Blocking B7-H4 or depleting B7-H4+ tumor macrophages may represent novel strategies to enhance T cell tumor immunity in cancer.
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kryczek
authors.forename: Linhua
authors.initials: L
authors.lastname: Zou
authors.forename: Paulo
authors.initials: P
authors.lastname: Rodriguez
authors.forename: Gefeng
authors.initials: G
authors.lastname: Zhu
authors.forename: Shuang
authors.initials: S
authors.lastname: Wei
authors.forename: Peter
authors.initials: P
authors.lastname: Mottram
authors.forename: Michael
authors.initials: M
authors.lastname: Brumlik
authors.forename: Pui
authors.initials: P
authors.lastname: Cheng
authors.forename: Tyler
authors.initials: T
authors.lastname: Curiel
authors.forename: Leann
authors.initials: L
authors.lastname: Myers
authors.forename: Andrew
authors.initials: A
authors.lastname: Lackner
authors.forename: Xavier
authors.initials: X
authors.lastname: Alvarez
authors.forename: Augusto
authors.initials: A
authors.lastname: Ochoa
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics*; D060890:B7-H1 Antigen; D015415:Biomarkers; D002277:Carcinoma / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D008264:Macrophages / Q000145:classification / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D014407:Tumor Cells, Cultured; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D015415:Biomarkers; C423236:CD274 protein, human; D015850:Interleukin-6; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human; D016753:Interleukin-10