PD-1hi Identifies a Novel Regulatory B-cell Population in Human Hepatoma That Promotes Disease Progression

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 · 发表于：Cancer Discovery · 年份：2016 · DOI：10.1158/2159-8290.cd-15-1408 · 被引用次数：345 · 研究领域：Cancer Immunotherapy and Biomarkers、CAR-T cell therapy research、Immune Cell Function and Interaction

UNLABELLED: 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-1(hi) B cells exhibited a unique CD5(hi)CD24(-/+)CD27(hi/+)CD38(dim) phenotype different from the phenotype of conventional CD24(hi)CD38(hi) peripheral regulatory B cells. TLR4-mediated BCL6 upregulation was crucial for PD-1(hi) 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-1(hi) 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-1(hi) 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-1(hi) B cells, which operate via IL10-dependent pathways upon interacting with PD-L1 to cause T-cell dysfunction and foster disease pro...