B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma.
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.
Kryczek
Ilona
I
Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Zou
Linhua
L
Rodriguez
Paulo
P
Zhu
Gefeng
G
Wei
Shuang
S
Mottram
Peter
P
Brumlik
Michael
M
Cheng
Pui
P
Curiel
Tyler
T
Myers
Leann
L
Lackner
Andrew
A
Alvarez
Xavier
X
Ochoa
Augusto
A
Chen
Lieping
L
Zou
Weiping
W
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
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