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.

Antigen-Specific Immunity and Cross-Priming by Epithelial Ovarian Carcinoma-Induced CD11b+Gr-1+ Cells

“…Further investigation into the function of B7-H1 in immunostimulatory CD11b + Gr-1 + cells is necessary, because its function in CD11b + Gr-1 + cells and in MDSCs might be completely different. In addition, B7-H4 has been shown to be involved in suppression in human ovarian cancer (47). Although the surface expression of B7-H4 in immunostimulatory CD11b + Gr-1 + cells cannot be detected, the correlation between B7-H4 and CD11b + Gr-1 + cells was illustrated by B7-H4 knockout mice in Listeria infection (48) as well as by soluble form of B7-H4 in rheumatoid arthritis (49).…”

Inflammatory regulatory T cells in the microenvironments of ulcerative colitis and colon carcinoma

“…Peripheral blood, ulcerative colitis tissues, colon carcinoma, and ovarian carcinoma tissues 9,[38][39][40][41] were collected for this study. Because the tissues associated with ulcerative colitis cannot objectively be called "normal", we took grossly adjacent tissues from at least 5 cm away from active colitic and colon cancer locations.…”

IL-10/TGF-β–Modified Macrophages Induce Regulatory T Cells and Protect against Adriamycin Nephrosis

“…11,12 It has been reported that B7-H4 is expressed by tumor-associated macrophages in human ovarian carcinoma. 13,14 It has also been shown that Tregs can convey suppressive activity to macrophages by stimulating B7-H4 expression through IL-10. 15 Antigen-specific T cell responses are impaired in mice treated with a B7-H4Ig fusion protein.…”