Ten-eleven translocation-2 inactivation restrains IL-10-producing regulatory B cells to enable antitumor immunity in hepatocellular carcinoma
Ten-eleven translocation-2 inactivation restrains IL-10-producing regulatory B cells to enable antitumor immunity in hepatocellular carcinoma
复制标题
10-11 易位-2 失活抑制产生 IL-10- 的调节性 B 细胞，从而在肝细胞癌中实现抗肿瘤免疫
DOI：
10.1002/hep.32442
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发表时间：
2022-04-27
期刊：
影响因子：
13.5
通讯作者：
Cai, Jiabin
中科院分区：
文献类型：
--
作者：
Lu, Zhou;Liu, Ronghua;Cai, Jiabin
产生IL-10的调节性B细胞（IL-10（+）B细胞）是一种占优势的调节性B细胞（布雷格）亚群，促进肿瘤进展。然而，其在HCC中产生的机制知之甚少。TET 2是B细胞中一种重要的表观遗传调控酶，通过催化5-甲基胞嘧啶脱甲基为5-羟甲基胞嘧啶（5 hmC）来调控基因表达。本研究旨在探讨TET 2在肝细胞癌IL-10（+）B细胞生成中的作用及其临床应用前景。方法和结果由HCC微环境的氧化应激触发的B细胞中的TET 2活化促进IL-10表达，而Tet 2缺陷的B细胞的过继转移抑制HCC进展。芳基烃受体是TET 2羟基化II 10所必需的。此外，B细胞中高水平的IL-10、TET 2和5 hmc表明HCC患者预后不良。此外，我们使用B细胞中的5 hmc测定TET 2活性以评估抗程序性死亡1（抗PD-1）疗法的功效。值得注意的是，B细胞中的TET 2抑制促进抗肿瘤免疫，以改善HCC的抗PD-1治疗。结论我们的研究结果提出了一种TET 2依赖的表观遗传干预，靶向HCC进展过程中IL-10（+）B细胞的生成，并确定抑制TET 2活性是一种有希望的HCC免疫检查点抑制剂联合治疗方法。
Background and Aims IL-10-producing regulatory B cells (IL-10(+)B cells), a dominant regulatory B cell (Breg) subset, foster tumor progression. However, the mechanisms underlying their generation in HCC are poorly understood. Ten-eleven translocation-2 (TET2), a predominant epigenetic regulatory enzyme in B cells, regulates gene expression by catalyzing demethylation of 5-methylcytosine into 5-hydroxymethyl cytosine (5hmC). In this study, we investigated the role of TET2 in IL-10(+)B cell generation in HCC and its prospects for clinical application. Approach and Results TET2 activation in B cells triggered by oxidative stress from the HCC microenvironment promoted IL-10 expression, whereas adoptive transfer of Tet2-deficient B cells suppressed HCC progression. The aryl hydrocarbon receptor is required for TET2 to hydroxylate Il10. In addition, high levels of IL-10, TET2, and 5hmc in B cells indicate poor prognosis in patients with HCC. Moreover, we determined TET2 activity using 5hmc in B cells to evaluate the efficacy of anti-programmed death 1 (anti-PD-1) therapy. Notably, TET2 inhibition in B cells facilitates antitumor immunity to improve anti-PD-1 therapy for HCC. Conclusions Our findings propose a TET2-dependent epigenetic intervention targeting IL-10(+)B cell generation during HCC progression and identify the inhibition of TET2 activity as a promising combination therapy with immune checkpoint inhibitors for HCC.