Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma

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.