Lu Zhou, Liu Ronghua, Wang Yining, Jiao Mengxia, Li Zhongchen, Wang Zhiqiang, Huang Cheng, Shi Guoming, Ke Aiwu, Wang Luman, Fu Ying, Xia Jie, Wen Haoyu, Zhou Jian, Wang Xiaoying, Ye Dan, Fan Jia, Chu Yiwei, Cai Jiabin
Department of Liver Surgery and Transplantation , Liver Cancer Institute , Zhongshan Hospital, Fudan University , Shanghai , P.R. China.
Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education) , Zhongshan Hospital, Fudan University , Shanghai , P.R. China.
Hepatology. 2023 Mar 1;77(3):745-759. doi: 10.1002/hep.32442. Epub 2023 Feb 17.
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.
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.
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.
产生白细胞介素10的调节性B细胞（IL-10+B细胞）是调节性B细胞（Breg）的主要亚群，可促进肿瘤进展。然而，肝癌中其产生的潜在机制尚不清楚。TET2是B细胞中主要的表观遗传调节酶，通过催化5-甲基胞嘧啶去甲基化为5-羟甲基胞嘧啶（5hmC）来调节基因表达。在本研究中，我们探讨了TET2在肝癌IL-10+B细胞产生中的作用及其临床应用前景。
肝癌微环境中的氧化应激触发B细胞中TET2的激活，促进IL-10表达，而转输Tet2缺陷型B细胞可抑制肝癌进展。芳烃受体是TET2使Il10羟基化所必需的。此外，B细胞中高水平的IL-10、TET2和5hmc表明肝癌患者预后不良。此外，我们利用B细胞中的5hmC测定TET2活性，以评估抗程序性死亡1（抗PD-1）治疗的疗效。值得注意的是，抑制B细胞中的TET2可促进抗肿瘤免疫，从而改善肝癌的抗PD-1治疗。
我们的研究结果提出了一种在肝癌进展过程中针对IL-10+B细胞产生的TET2依赖性表观遗传干预措施，并确定抑制TET2活性是一种与免疫检查点抑制剂联合治疗肝癌的有前景的方法。
