下调和上调
调节性B细胞
白细胞介素10
癌症研究
生物
细胞
人口
免疫学
B细胞
免疫系统
癌症
医学
基因
抗体
遗传学
环境卫生
作者
Christos Xiao,Xiang‐Ming Lao,Minmin Chen,Ruixian Liu,Wei Yuan,Fang‐Zhu Ouyang,Dong‐Ping Chen,Xiaoyu Zhao,Qiyi Zhao,Xuefeng Li,Chuan-Lu Liu,Limin Zheng,Dong‐Ming Kuang
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2016-02-29
卷期号:6 (5): 546-559
被引量:325
标识
DOI:10.1158/2159-8290.cd-15-1408
摘要
Abstract B cells often constitute abundant cellular components in human tumors. Regulatory B cells that are functionally defined by their ability to produce IL10 downregulate inflammation and control T-cell immunity. Here, we identified a protumorigenic subset of B cells that constitutively expressed higher levels of programmed cell death-1 (PD-1) and constituted ∼10% of all B cells in advanced-stage hepatocellular carcinoma (HCC). These PD-1hi B cells exhibited a unique CD5hiCD24−/+CD27hi/+CD38dim phenotype different from the phenotype of conventional CD24hiCD38hi peripheral regulatory B cells. TLR4-mediated BCL6 upregulation was crucial for PD-1hi B-cell induction by HCC environmental factors, and that effect was abolished by IL4-elicited STAT6 phosphorylation. Importantly, upon encountering PD-L1+ cells or undergoing PD-1 triggering, PD-1hi B cells acquired regulatory functions that suppressed tumor-specific T-cell immunity and promoted cancer growth via IL10 signals. Our findings provide significant new insights for human cancer immunosuppression and anticancer therapies regarding PD-1/PD-L1. Significance: We identify a novel protumorigenic PD-1hi B-cell subset in human HCC that exhibits a phenotype distinct from that of peripheral regulatory B cells. TLR4-mediated BCL6 upregulation is critical for induction of PD-1hi B cells, which operate via IL10-dependent pathways upon interacting with PD-L1 to cause T-cell dysfunction and foster disease progression. Cancer Discov; 6(5); 546–59. ©2016 AACR. See related commentary by Ren et al., p. 477. This article is highlighted in the In This Issue feature, p. 461
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