Tumor-derived exosomal HMGB1 fosters hepatocellular carcinoma immune evasion by promoting TIM-1+ regulatory B cell expansion
Tumor-derived exosomal HMGB1 fosters hepatocellular carcinoma immune evasion by promoting TIM-1+ regulatory B cell expansion
复制标题
肿瘤源性外泌体 HMGB1 通过促进 TIM-1( ) 调节性 B 细胞扩增促进肝细胞癌免疫逃避
DOI：
10.1186/s40425-018-0451-6
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发表时间：
2018-12-10
影响因子：
10.9
通讯作者：
Chen, Guihua
中科院分区：
文献类型：
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作者：
Ye, Linsen;Zhang, Qi;Chen, Guihua
调节性B细胞(Breg细胞)是B细胞亚群中的一种，可侵袭实体瘤，在不同的肿瘤微环境中表现出不同的表型。方法采用流式细胞术检测51例肝细胞癌患者外周血中TIM-1(+)Breg细胞的表达水平、表型及功能。总体生存和无病生存的Kaplan-Meier图采用对数等级检验。体外分离、刺激和/或培养TIM-1(+)Breg细胞和CD8(+)T细胞进行功能检测。分离外切体和B细胞，体外培养Tim-1(+)Breg细胞。结果肝癌患者肿瘤组织中Tim-1(+)Breg细胞的浸润率明显高于瘤周组织。浸润性TIM-1(+)Breg细胞表现为CD5(高)CD24(-)CD27(-/+)CD38(+/高)表型，高水平表达免疫抑制细胞因子IL-10，对CD8(+)T细胞有较强的抑制活性。经肿瘤外切体激活的B细胞强烈表达TIM-1蛋白，对CD8(+)T细胞具有类似于从肝癌组织分离的TIM-1(+)Breg细胞的抑制活性。此外，TIM-1(+)Breg细胞在肿瘤中的积聚与疾病的进展、预测肝细胞癌的早期复发和降低患者的生存期有关。外体来源的HMGB1通过Toll样受体(TLR)2/4和丝裂原活化蛋白激酶(MAPK)信号通路激活B细胞并促进Tim-1(+)Breg细胞的增殖。结论揭示了Tim-1(+)Breg细胞介导的免疫逃逸在肝癌中的新机制，为利用这些新的外体HMGB1-TLR2/4-MAPK途径防治肝癌的免疫耐受特性提供了功能证据。
BackgroundRegulatory B (Breg) cells represent one of the B cell subsets that infiltrate solid tumors and exhibit distinct phenotypes in different tumor microenvironments. However, the phenotype, function and clinical relevance of Breg cells in human hepatocellular carcinoma (HCC) are presently unknown.MethodsFlow cytometry analyses were performed to determine the levels, phenotypes and functions of TIM-1(+)Breg cells in samples from 51 patients with HCC. Kaplan-Meier plots for overall survival and disease-free survival were generated using the log-rank test. TIM-1(+)Breg cells and CD8(+) T cells were isolated, stimulated and/or cultured in vitro for functional assays. Exosomes and B cells were isolated and cultured in vitro for TIM-1(+)Breg cell expansion assays.ResultsPatients with HCC showed a significantly higher TIM-1(+)Breg cell infiltration in their tumor tissue compared with the paired peritumoral tissue. The infiltrating TIM-1(+)Breg cells showed a CD5(high)CD24(-)CD27(-/+)CD38(+/high) phenotype, expressed high levels of the immunosuppressive cytokine IL-10 and exhibited strong suppressive activity against CD8(+) T cells. B cells activated by tumor-derived exosomes strongly expressed TIM-1 protein and were equipped with suppressive activity against CD8(+) T cells similar to TIM-1(+)Breg cells isolated from HCC tumor tissue. Moreover, the accumulation of TIM-1(+)Breg cells in tumors was associated with advanced disease stage, predicted early recurrence in HCC and reduced HCC patient survival. Exosome-derived HMGB1 activated B cells and promoted TIM-1(+)Breg cell expansion via the Toll like receptor (TLR) 2/4 and mitogen-activated protein kinase (MAPK) signaling pathways.ConclusionsOur results illuminate a novel mechanism of TIM-1(+)Breg cell-mediated immune escape in HCC and provide functional evidence for the use of these novel exosomal HMGB1-TLR2/4-MAPK pathways to prevent and to treat this immune tolerance feature of HCC.