Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China. State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
Cancer Discov. 2016 May;6(5):546-59. doi: 10.1158/2159-8290.CD-15-1408. Epub 2016 Feb 29.
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.
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 progression. Cancer Discov; 6(5); 546-59. ©2016 AACR.See related commentary by Ren et al., p. 477This article is highlighted in the In This Issue feature, p. 461.
B 细胞经常构成人类肿瘤中丰富的细胞成分。功能上通过产生 IL10 而下调炎症并控制 T 细胞免疫的调节性 B 细胞。在这里，我们鉴定了一种促肿瘤发生的 B 细胞亚群，其程序性细胞死亡受体 1（PD-1）表达水平较高，在晚期肝细胞癌（HCC）中占所有 B 细胞的约 10％。这些 PD-1（高）B 细胞表现出独特的 CD5（高）CD24（-/+）CD27（高/+）CD38（低）表型，与传统的 CD24（高）CD38（高）外周调节性 B 细胞的表型不同。TLR4 介导的 BCL6 上调对于 HCC 环境因素诱导的 PD-1（高）B 细胞诱导至关重要，而该作用被 IL4 诱导的 STAT6 磷酸化所消除。重要的是，当遇到 PD-L1（+）细胞或经历 PD-1 触发时，PD-1（高）B 细胞获得了抑制肿瘤特异性 T 细胞免疫并通过 IL10 信号促进癌症生长的调节功能。我们的研究结果为 PD-1/PD-L1 提供了有关人类癌症免疫抑制和抗癌治疗的重要新见解。
我们在人 HCC 中鉴定出一种新型促肿瘤发生的 PD-1（高）B 细胞亚群，其表型与外周调节性 B 细胞不同。TLR4 介导的 BCL6 上调对于诱导 PD-1（高）B 细胞至关重要，该细胞在与 PD-L1 相互作用时通过 IL10 依赖性途径发挥作用，导致 T 细胞功能障碍并促进疾病进展。癌症发现；6（5）；546-59。 ©2016 AACR.请参阅相关评论文章，第 477 页Ren 等人，p. 477 本文在本期特色文章中突出显示，第 461 页。
