Lkb1 aggravates diffuse large B-cell lymphoma by promoting the function of Treg cells and immune escape.
Lkb1 aggravates diffuse large B-cell lymphoma by promoting the function of Treg cells and immune escape.
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Lkb1通过促进Treg细胞功能和免疫逃逸加重弥漫性大B细胞淋巴瘤
DOI：
10.1186/s12967-022-03588-0
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发表时间：
2022-08-19
影响因子：
7.4
通讯作者：
Ji, Chunyan
中科院分区：
文献类型：
--
作者：
Su, Xiuhua;Sun, Tao;Li, Meng;Xia, Yuan;Li, Mingying;Wang, Dongmei;Lu, Fei;Ye, Jingjing;Ji, Chunyan
关键词：
调节性T细胞（Tcells）诱导免疫应答，并可能有助于肿瘤的免疫逃逸。肿瘤中Tcl 3的积累代表了抗肿瘤免疫和免疫治疗的关键障碍。然而，描述TdR在淋巴瘤中的作用的相互矛盾的结果需要进一步研究。弥漫性大B细胞淋巴瘤（DLBCL）中Tcl 3改变的确切特征和机制尚未完全了解。在这项研究中，我们分析的机制，观察到的改变，在DLBCL和检查Lkb 1的表达对人类TCLs的免疫抑制功能的影响。采用流式细胞术和免疫荧光法检测DLBCL患者和对照组外周血和淋巴结中Tcl 4和效应Tcl 4的比例。采用体外培养法检测TGFAP对两组小鼠的免疫抑制作用。采用RT-PCR和WES微蛋白技术检测Lkb 1在两组中的转录水平和蛋白表达。慢病毒载体的构建，以探讨TcR的功能变化与稳定的上调和下调Lkb 1。最后，建立了人源化小鼠淋巴瘤模型，以研究Lkb 1在DLBCL发病机制中的作用。DLBCL患者外周血和肿瘤组织中THBG的数量明显高于健康对照组，治疗后THBG的数量明显下降。DLBCL患者的T细胞具有多种增强的功能，包括增强对CD 8+细胞毒性T细胞（CTL）对肿瘤细胞的抑制，增强对CD 8 +CTL分泌颗粒酶的抑制，以及抑制CD 8 +CTL脱颗粒。发现DLBCL患者的T细胞中Lkb 1表达上调。此外，Lkb 1通过调节甲羟戊酸途径在DLBCL中促进Treg免疫抑制功能。最后，在DLBCL小鼠模型中，TcB中Lkb 1的缺失抑制了肿瘤生长并促进了抗肿瘤免疫。这些发现证实了Lkb 1调节的TcR在DLBCL的免疫逃逸中是至关重要的，这强调了Lkb 1是DLBCL免疫治疗的潜在靶点。在线版本包含补充材料，可通过10.1186/s12967-022-03588-0获得。
Regulatory T cells (Tregs) induce immune responses and may contribute to immune escape in tumors. Accumulation of Tregs in tumors represents a critical barrier to anti-tumor immunity and immunotherapy. However, conflicting results describing the role of Tregs in lymphoma warrant further investigation. The precise features and mechanisms underlying the alteration in Tregs in diffuse large B-cell lymphoma (DLBCL) are not well understood yet. In this study, we analyzed the mechanism underlying the observed alterations in Tregs in DLBCL and examined the effect of Lkb1 expression on the immunosuppressive function of human Tregs. Flow cytometry and immunofluorescence were used to analyze the proportion of Tregs and effector Tregs in the peripheral blood and lymph nodes of patients with DLBCL and control group. In vitro culture assays were used to analyze the immunosuppressive function of Tregs in the two groups. Transcriptome sequencing was performed to analyze the differentially expressed genes in the two groups, and the transcription level and protein expression of Lkb1 in the two groups were detected using RT-PCR and WES microprotein technology. Lentiviral vectors were constructed to explore the functional changes of Tregs with stable upregulation and downregulation of Lkb1. Finally, a humanized murine lymphoma model was established to study the function of Lkb1 in Tregs in the pathogenesis of DLBCL. The number of Tregs was found to be dramatically increased in peripheral blood and tumor tissue in DLBCL patients compared with that in healthy controls, and decreased after treatment. Tregs from DLBCL patients exhibited multiple enhanced functions, including increased inhibition of CD8+cytotoxic T cells (CTL) against tumor cells, enhanced suppression of CD8+CTL secretion of granular enzyme, and suppression of CD8+CTL degranulation. Lkb1 was found to be upregulated in Tregs of DLBCL patients. Furthermore, Lkb1 contributes to Treg immunosuppressive function in DLBCL by regulating the mevalonate pathway. Finally, deletion of Lkb1 in Tregs suppressed tumor growth and promoted anti-tumor immunity in a DLBCL murine model. These findings confirmed that Lkb1-regulated Tregs are critical for immune escape in DLBCL, which emphasizes that Lkb1 is a potential target for the immunotherapy of DLBCL. The online version contains supplementary material available at 10.1186/s12967-022-03588-0.
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影响因子：
9
作者：
Lacher, Sonja M.;Bruttger, Julia;Waisman, Ari
通讯作者：
Waisman, Ari
CD127表达与FOXP3和人类CD4+ T Reg细胞的抑制功能成反比。
DOI：
10.1084/jem.20060772
发表时间：
2006-07-10
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1097/pai.0000000000000335
发表时间：
2017-09-01
影响因子：
1.6
作者：
El-Dien, Marwa M. Serag;Abdou, Asmaa G.;Kora, Mona Abd El-Hamid M.
通讯作者：
Kora, Mona Abd El-Hamid M.
影响因子：
16.6
作者：
Franklin, J. Matthew;Ghosh, Rajarshi P.;Liphardt, Jan T.
通讯作者：
Liphardt, Jan T.
影响因子：
11.2
作者：
Gobert, Michael;Treilleux, Isabelle;Menetrier-Caux, Christine
通讯作者：
Menetrier-Caux, Christine