Kryczek Ilona, Wei Shuang, Zhu Gefeng, Myers Leann, Mottram Peter, Cheng Pui, Chen Lieping, Coukos George, Zou Weiping
Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
Cancer Res. 2007 Sep 15;67(18):8900-5. doi: 10.1158/0008-5472.CAN-07-1866.
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.
B7-H4是最近发现的一种B7家族成员。我们之前的研究表明，卵巢肿瘤及相关巨噬细胞表达B7-H4；肿瘤中B7-H4阳性巨噬细胞和CD4+CD25+FOXP3+调节性T细胞（Treg细胞）可抑制肿瘤相关抗原特异性T细胞免疫。为了确定肿瘤环境中B7-H4、巨噬细胞和Treg细胞之间的病理关系，除了Treg细胞数量外，我们还对103例卵巢癌患者肿瘤及肿瘤相关巨噬细胞中的B7-H4表达进行了定量分析。我们观察到，巨噬细胞中B7-H4的表达强度与肿瘤中Treg细胞数量显著相关。此外，Treg细胞和巨噬细胞B7-H4，而非肿瘤B7-H4，均与患者预后呈负相关。肿瘤Treg细胞可使巨噬细胞自发产生白细胞介素（IL）-10和IL-6。肿瘤巨噬细胞通过IL-10和IL-6以自分泌方式刺激B7-H4表达。我们之前的研究表明，肿瘤相关巨噬细胞自发产生趋化因子CCL22以介导Treg细胞向肿瘤的迁移，且Treg细胞可在包括巨噬细胞在内的抗原呈递细胞（APC）上诱导B7-H4表达。总之，我们的数据支持以下观点：Treg细胞与巨噬细胞之间存在机制性相互作用，且在人类卵巢癌中Treg细胞可能通过诱导B7-H4将抑制活性传递给APC。
