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.
Kryczek
Ilona
I
Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
Wei
Shuang
S
Zhu
Gefeng
G
Myers
Leann
L
Mottram
Peter
P
Cheng
Pui
P
Chen
Lieping
L
Coukos
George
G
Zou
Weiping
W
D000938:Antigen-Presenting Cells / Q000276:immunology; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000276:immunology*; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D010051:Ovarian Neoplasms / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1
D018122:B7-1 Antigen; D015850:Interleukin-6; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human; D016753:Interleukin-10