Chemokine (C-X-C Motif) Receptor 3-Positive B Cells Link Interleukin-17 Inflammation to Protumorigenic Macrophage Polarization in Human Hepatocellular Carcinoma
Chemokine (C-X-C Motif) Receptor 3-Positive B Cells Link Interleukin-17 Inflammation to Protumorigenic Macrophage Polarization in Human Hepatocellular Carcinoma
复制标题
趋化因子（C-X-C 基序）受体 3 阳性 B 细胞将白细胞介素 17 炎症与人肝细胞癌中促肿瘤巨噬细胞极化联系起来
DOI：
10.1002/hep.28020
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发表时间：
2015-12-01
期刊：
影响因子：
13.5
通讯作者：
Kuang, Dong-Ming
中科院分区：
文献类型：
--
作者：
Liu, Rui-Xian;Wei, Yuan;Kuang, Dong-Ming
B细胞始终代表肿瘤中丰富的细胞组分;然而，支持B细胞在人类癌症免疫发病机制中的作用的直接证据缺乏，其运输机制的具体知识也是如此。在此，我们证明趋化因子（C-X-C基序）受体3阳性（CXCR 3（+））B细胞占人肝细胞癌（HCC）浸润B细胞的约45%，并且它们的水平与HCC的早期复发呈正相关。这些细胞选择性地聚集在HCC的侵袭边缘，并经历进一步的体细胞超突变和分泌免疫球蛋白G的浆细胞分化。促炎性白细胞介素-17（+）细胞对于诱导上皮细胞来源的CXCR 3配体CXCL 9、CXCL 10和CXCL 11是重要的，其随后促进CXCR 3（+）B细胞的顺序募集和进一步成熟。更重要的是，我们提供的证据表明，CXCR 3（+）B细胞，而不是它们的CXCR 3（-）对应物，可能在免疫球蛋白G依赖性途径中起作用，以诱导人HCC中的M2 B巨噬细胞极化。B细胞的耗竭显著抑制了M2 B极化和肿瘤相关巨噬细胞的促肿瘤活性，并恢复了这些细胞体内抗肿瘤白细胞介素-12的产生。结论：选择性募集CXCR 3（+）B细胞可在肿瘤环境中连接促炎性白细胞介素-17反应和促肿瘤发生巨噬细胞极化，阻断CXCR 3（+）B细胞迁移或功能可能有助于击败HCC。
B cells consistently represent abundant cellular components in tumors; however, direct evidence supporting a role for B cells in the immunopathogenesis of human cancers is lacking, as is specific knowledge of their trafficking mechanisms. Here, we demonstrate that chemokine (C-X-C motif) receptor 3-positive (CXCR3(+)) B cells constitute approximately 45% of B-cell infiltrate in human hepatocellular carcinoma (HCC) and that their levels are positively correlated with early recurrence of HCC. These cells selectively accumulate at the invading edge of HCC and undergo further somatic hypermutation and immunoglobulin G-secreting plasma cell differentiation. Proinflammatory interleukin-17(+) cells are important for the induction of epithelial cell-derived CXCR3 ligands CXCL9, CXCL10, and CXCL11, which subsequently promote the sequential recruitment and further maturation of CXCR3(+) B cells. More importantly, we provide evidence that CXCR3(+) B cells, but not their CXCR3(-) counterparts, may operate in immunoglobulin G-dependent pathways to induce M2b macrophage polarization in human HCC. Depletion of B cells significantly suppresses M2b polarization and the protumorigenic activity of tumor-associated macrophages and restores the production of antitumorigenic interleukin-12 by those cells in vivo. Conclusion: Selective recruitment of CXCR3(+) B cells bridges proinflammatory interleukin-17 response and protumorigenic macrophage polarization in the tumor milieu, and blocking CXCR3(+) B-cell migration or function may help defeat HCC.