α1-Acid Glycoprotein Enhances the Immunosuppressive and Protumor Functions of Tumor-Associated Macrophages
α1-Acid Glycoprotein Enhances the Immunosuppressive and Protumor Functions of Tumor-Associated Macrophages
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DOI：
10.1158/0008-5472.can-20-3471
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发表时间：
2021-09-01
期刊：
影响因子：
11.2
通讯作者：
Maruyama, Toru
中科院分区：
文献类型：
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作者：
Matsusaka, Kotaro;Fujiwara, Yukio;Maruyama, Toru
癌症患者血液中的急性期蛋白α(1)-酸性糖蛋白（AGP，即血清类黏蛋白）水平会升高。尽管在炎症和肿瘤发生的情况下，AGP由免疫细胞衍生的细胞因子刺激肝细胞产生，但AGP在肿瘤发生和肿瘤进展中的作用仍不明确。在本研究中，我们发现AGP通过诱导巨噬细胞中程序性死亡配体1（PD-L1）的表达和白细胞介素6（IL6）的产生，直接促进肿瘤发展。AGP刺激可通过激活信号转导及转录激活因子1（STAT1），诱导人单核细胞衍生的巨噬细胞表达PD-L1，而AGP对肿瘤细胞中PD-L1的表达没有直接影响。AGP还可诱导巨噬细胞产生IL6，IL6通过IL6受体介导的STAT3激活，刺激肿瘤细胞增殖。此外，给AGP基因敲除小鼠注射AGP，可模拟肿瘤相关巨噬细胞（TAM）对肿瘤进展的影响。AGP减少了T细胞分泌干扰素γ（IFNγ），并增强了皮下肿瘤组织中STAT3的激活。另外，AGP通过与Toll样受体4（TLR4）的共受体CD14结合并诱导TLR4信号通路，调节巨噬细胞中PD-L1的表达和IL6的产生。这些结果首次证明AGP通过与TAM相互作用直接参与肿瘤发生，AGP可能是抗癌治疗的一个靶分子。
意义：AGP介导的抗肿瘤免疫抑制通过诱导TAM中PD-L1的表达和IL6的产生，促进肿瘤进展。
Blood levels of acute-phase protein alpha(1)-acid glycoprotein (AGP, orosmucoid) increase in patients with cancer. Although AGP is produced from hepatocytes following stimulation by immune cell-derived cytokines under conditions of inflammation and tumorigenesis, the functions of AGP in tumorigenesis and tumor progression remain unknown. In the present study, we revealed that AGP contributes directly to tumor development by induction of programmed death ligand 1 (PD-L1) expression and IL6 production in macrophages. Stimulation of AGP induced PD-L1 expression in both human monocyte-derived macrophages through STAT1 activation, whereas AGP had no direct effect on PD-L1 expression in tumor cells. AGP also induced IL6 production from macrophages, which stimulated proliferation in tumor cells by IL6R-mediated activation of STAT3. Furthermore, administration of AGP to AGP KO mice phenocopied effects of tumor-associated macrophages (TAM) on tumor progression. AGP decreased IFN gamma secretion from T cells and enhanced STAT3 activation in subcutaneous tumor tissues. In addition, AGP regulated PD-L1 expression and IL6 production in macrophages by binding with CD14, a coreceptor for Toll-like receptor 4 (TLR4), and inducing TLR4 signaling. These results provide the first evidence that AGP is directly involved in tumorigenesis by interacting with TAMs and that AGP might be a target molecule for anticancer therapy.Significance: AGP-mediated suppression of antitumor immunity contributes to tumor progression by inducing PD-L1 expression and IL6 production in TAMs.