B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma
Open accessAbstract
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.
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In animal models, introducing B7-1 into tumors or blocking inhibitory B7 family members reduces tumor growth or causes spontaneous tumor rejection.
“Animal model studies have shown that introduction of B7-1 into tumors by transfection or blockade of inhibitory B7 family members can reduce tumor growth or result in spontaneous tumor rejection in vivo [7–13].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [10]
In the tumor microenvironment, stimulatory and inhibitory B7 family members are imbalanced, with high inhibitory and low stimulatory expression.
“There is an active imbalance between stimulatory and inhibitory B7 family members in the tumor microenvironment [1,3,7,8].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [10]
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- Authors
- Kryczek, I., Zou, L., Rodriguez, P., Zhu, G., Wei, S., Mottram, P., Brumlik, M., Cheng, P., Curiel, T., Myers, L., Lackner, A., Alvarez, X., Ochoa, A., Chen, L., & Zou, W.
- Affiliations
- Tulane University (US)
- 3Louisianna State University Health Sciences Center, New Orleans, LA 70112
- Johns Hopkins University (US)
- Louisiana State University Health Sciences Center New Orleans (US)
- ORCID
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2006-04-10
- Volume
- 203
- Issue
- 4
- Pages
- 871-881
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2118300
- OpenAlex
- W2110836981
- Cited by
- 748
- References
- 57
- Citations by year
- 2026: 15 · 2025: 22 · 2024: 30 · 2023: 30 · 2022: 54 · 2021: 29 · 2020: 34 · 2019: 35 · 2018: 30 · 2017: 39 · 2016: 43 · 2015: 43 · 2014: 37 · 2013: 46 · 2012: 41
- FWCI
- 16.44
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA092562, CA099985, CA 97085, CA 092562, R01CA097085, R21CA100227, R01CA099985, CA 100227)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- B7-H4, tumor-associated macrophages, ovarian carcinoma, T cell suppression, tumor microenvironment, interleukin-6, IL-10, GM-CSF, IL-4, PD-L1, arginase, inducible nitric oxide synthase, tumor immunosuppression, tumor regression
- MeSH terms
- Animals, Antigens, Neoplasm, Carcinoma, Female, Humans, Macrophages, Ovarian Neoplasms, T-Lymphocytes, Tumor Cells, Cultured, Biomarkers, Antigens, CD, Interleukin-6, Immunophenotyping, Mice, SCID, Mice, Inbred NOD, Interleukin-10, B7-1 Antigen, Mice, B7-H1 Antigen, V-Set Domain-Containing T-Cell Activation Inhibitor 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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