B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma

By Ilona Kryczek, L. Zou, P. Rodriguez, G. Zhu, Shuang Wei, P. Mottram, M. Brumlik, P. Cheng, T. Curiel, L. Myers and 5 more. Journal of Experimental Medicine, 2006

761 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/fd467299c039c98ed5018c6823aafbaccfa069ba

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Lisa M. Coussens
2. A. Mantovani
3. B. Ruffell
4. P. Allavena
5. Guido Kroemer
6. J. Pollard
7. C. Garlanda
8. W. Zou

In Oncology

1. Lisa M. Coussens
2. A. Mantovani
3. B. Ruffell
4. P. Allavena
5. J. Pollard
6. Guido Kroemer
7. W. Zou
8. C. Garlanda

Citations in the corpus

• Tumor-associated macrophages: from mechanisms to therapy (2014, background): “Moreover, the inhibition of B7-H4 restores the stimulating function of TAMs and contributes to tumor regression (Kryczek et al., 2006).”
• Accessories to the crime: functions of cells recruited to the tumor microenvironment. (2012, neutral): “In human TAMs, suppression of CD8 + T cells can occur independent of L-arginine metabolism (Kryczek et al., 2006) and may instead rely on macrophage expression of ligands for T cell costimulatory receptors that mediate T cell inhibition (Topalian et al., 2012), as has been described for…”
• Immunosuppressive strategies that are mediated by tumor cells. (2007, background): “recently identified B7-H4 as a novel marker of a population of suppressor macrophages in human ovarian carcinoma (95).”
• Macrophage activation by endogenous danger signals (2008, background): “IL-10 not only subverts the development of classical macrophage activation responses but also stimulates macrophages to express B7-H4, a novel member of the B7 family of T cell co-stimulator molecules [146].”
• Tumor-infiltrating NY-ESO-1–specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer (2010, background): “Because IL-6, IL-10, and TGF-β are associated with immune suppression in ovarian cancer (16), we asked whether these cytokines are also involved in the induction of LAG-3PD-1 and LAG-3PD-1 cells.”
• Inhibitory B7-family molecules in the tumour microenvironment (2008, background): “B7-H4 remains an orphan ligand, although evidence indicates that a receptor can be induced and could function on T cell”
• Cancer despite immunosurveillance: immunoselection and immunosubversion (2006, background): “IL-6 and IL-10 have also been found to stimulate a B7-H4-expressing T-cell-suppressive macrophage population in patients with ovarian carcinom”
• The interaction of anticancer therapies with tumor-associated macrophages (2015, background): “Moreover, TAMs from HCC express the B7 family member B7H4 (Kryczek et al., 2006).”
• Differential Macrophage Programming in the Tumor Microenvironment (2012, neutral): “In contrast, suppression of CD8+ T cells by human TAMs can occur independent of L-arginine metabolism [34], and instead may rely on the B7 family of molecules as has been described for B7-H1 (PD-L1) in hepatocellular carcinoma [86], and B7-H4 in ovarian cancer [34].”
• Regulatory T cells, tumour immunity and immunotherapy (2006, background): “One possibility is that T Reg cells might condition APCs and enable them to express functional IL-10 (Ref”