Published online 10 April 2006 doi:10.1084/jem.20050930
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 4, 871-881
B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma
Ilona Kryczek1,2,
Linhua Zou1,2,
Paulo Rodriguez3,
Gefeng Zhu4,
Shuang Wei1,2,
Peter Mottram2,
Michael Brumlik2,
Pui Cheng2,
Tyler Curiel2,
Leann Myers2,
Andrew Lackner2,
Xavier Alvarez2,
Augusto Ochoa3,
Lieping Chen4, and
Weiping Zou1,2
1 Department of Surgery, University of Michigan, Ann Arbor, MI 48109
2 Tulane University Health Sciences Center, New Orleans, LA 70112
3 Louisianna State University Health Sciences Center, New Orleans, LA 70112
4 Department of Dermatology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD 21287
CORRESPONDENCE Weiping Zou: wzou{at}umich.edu
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.
Abbreviations used: cpm, counts per minute; iNOS, inducible nitric oxide synthase; MDC, myeloid dendritic cell; SDF, stromal-derived factor; TAA, tumor-associated antigen; T reg cell, T regulatory cell; VEGF, vascular endothelial growth factor.
L. Zou and P. Rodriguez contributed equally to this work.
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