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Relationship between B7-H4, Regulatory T Cells, and Patient Outcome in Human Ovarian Carcinoma

¹ Department of Surgery, University of Michigan, Ann Arbor, Michigan; ² Departments of Dermatology and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland; ³ Tulane University Health Science Center, New Orleans, Louisiana; and ⁴ Division of Gynecologic Oncology, University of Pennsylvania, Philadelphia, Pennsylvania

Requests for reprints: Weiping Zou, University of Michigan School of Medicine, C560B MSRB II, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0669. Phone: 734-763-6402; Fax: 734-763-0143; E-mail: wzou{at}umich.edu.

B7-H4 is a recently identified B7 family member. We previously showed that ovarian tumor and associated macrophages expressed B7-H4; tumor B7-H4⁺ macrophages and CD4⁺CD25⁺FOXP3⁺ regulatory T cells (Treg cells) suppressed tumor-associated antigen–specific T-cell immunity. To determine the pathologic relationship between B7-H4, macrophages, and Treg cells in the tumor environment, in addition to Treg cell numbers, we quantified B7-H4 expression in the tumor and tumor-associated macrophages in 103 patients with ovarian carcinoma. We observed that the intensity of B7-H4 expression in macrophages was significantly correlated with Treg cell numbers in the tumor. Further, both Treg cells and macrophage B7-H4, but not tumor B7-H4, were negatively associated with patient outcome. Tumor Treg cells enabled macrophages to spontaneously produce interleukin (IL)-10 and IL-6. Tumor macrophages stimulated B7-H4 expression in an autocrine manner through IL-10 and IL-6. Our previous work showed that tumor-associated macrophages spontaneously produced chemokine CCL22 to mediate Treg cell trafficking into tumor, and Treg cells induced B7-H4 on antigen-presenting cells (APC) including macrophages. Altogether, our data support the concept that there is a mechanistic interaction between Treg cells and macrophage, and that Treg cells may convey the suppressive activity to APCs through B7-H4 induction in human ovarian cancer. [Cancer Res 2007;67(18):8901–05]