BxPC-3-Derived Small Extracellular Vesicles Induce FOXP3+ Treg through ATM-AMPK-Sirtuins-Mediated FOXOs Nuclear Translocations
BxPC-3-Derived Small Extracellular Vesicles Induce FOXP3+ Treg through ATM-AMPK-Sirtuins-Mediated FOXOs Nuclear Translocations
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BxPC-3 衍生的小细胞外囊泡通过 ATM-AMPK-Sirtuins 介导的 FOXO 核易位诱导 FOXP3 Treg
DOI：
10.1016/j.isci.2020.101431
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发表时间：
2020-08
期刊：
影响因子：
5.8
通讯作者：
Cao Liping
中科院分区：
文献类型：
--
作者：
Shen Tao;Jia Shengnan;Ding Guoping;Ping Dongnan;Zhou Liangjing;Zhou Senhao;Cao Liping
胰腺导管腺癌（PDAC）的免疫治疗面临着严峻的挑战，特别是由于免疫原性差。癌细胞衍生的小细胞外囊泡（sEV）在损害免疫系统中起重要作用。然而，胰腺癌来源的sEV对T淋巴细胞的影响尚不清楚。在这里，我们研究了sEV处理的T淋巴细胞的表型和信号转导通路的变化。我们通过CyTOF鉴定了免疫检查点蛋白PD-1、PD-L1、CTLA 4和Tim-3的过表达以及sEV处理的T淋巴细胞中FOXP 3 + Treg簇的富集。基因组富集分析表明，sEV诱导的THBV-DNA损伤反应和代谢途径可能参与了THBV-DNA损伤。ATM、AMPK、SIRT 1、SIRT 2和SIRT 6在sEV处理的T淋巴细胞中依次激活，并且对于sEV上调FOXO 1A、FOXO 3A和FOXP 3的表达至关重要。我们的研究揭示了胰腺癌细胞来源的sEV对T淋巴细胞的影响和机制，并可能为开发PDAC治疗的免疫治疗策略提供见解。
Immunotherapy in pancreatic ductal adenocarcinoma (PDAC) treatment faces serious challenges, due particularly to the poor immunogenicity. Cancer cell-derived small extracellular vesicles (sEVs) play important roles in damaging the immune system. However, the effects of pancreatic cancer-derived sEVs on T lymphocytes are unknown. Here we investigated changes in phenotypes and signal transduction pathways in sEVs-treated T lymphocytes. We identified the overexpression of immune checkpoint proteins PD-1, PD-L1, CTLA4, and Tim-3 and the enrichment of FOXP3+ Treg cluster in sEVs-treated T lymphocytes by CyTOF. Gene set enrichment analysis revealed that DNA damage response and metabolic pathways might be involved in sEVs-induced Tregs. ATM, AMPK, SIRT1, SIRT2, and SIRT6 were activated sequentially in sEVs-treated T lymphocytes and essential for sEVs-upregulated expressions of FOXO1A, FOXO3A, and FOXP3. Our study reveals the impact and mechanism of pancreatic cancer cell-derived sEVs on T lymphocytes and may provide insights into developing immunotherapy strategies for PDAC treatment.
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DOI：
10.1146/annurev.pathol.3.121806.154305
发表时间：
2021-08
期刊：
Annual review of pathology
影响因子：
--
作者：
A. Maitra;R. Hruban
通讯作者：
A. Maitra;R. Hruban
影响因子：
--
作者：
C. Baecher-Allan;Julia A. Brown;G. Freeman;D. Hafler
通讯作者：
C. Baecher-Allan;Julia A. Brown;G. Freeman;D. Hafler
影响因子：
3.7
作者：
Wang X;Buechler NL;Martin A;Wells J;Yoza B;McCall CE;Vachharajani V
通讯作者：
Vachharajani V
影响因子：
5.6
作者：
Huber M;Brehm CU;Gress TM;Buchholz M;Alashkar Alhamwe B;von Strandmann EP;Slater EP;Bartsch JW;Bauer C;Lauth M
通讯作者：
Lauth M
影响因子：
50.5
作者：
Seufferlein, T.;Bachet, J. B.;Rougier, P.
通讯作者：
Rougier, P.