Cancer cell-derived exosomal circUSP7 induces CD8(+) T cell dysfunction and anti-PD1 resistance by regulating the miR-934/SHP2 axis in NSCLC.
Cancer cell-derived exosomal circUSP7 induces CD8(+) T cell dysfunction and anti-PD1 resistance by regulating the miR-934/SHP2 axis in NSCLC.
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癌细胞来源的外泌体 circUSP7 通过调节 NSCLC 中的 miR-934/SHP2 轴诱导 CD8(+) T 细胞功能障碍和抗 PD1 耐药性。
DOI：
10.1186/s12943-021-01448-x
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发表时间：
2021-11-09
期刊：
影响因子：
37.3
通讯作者：
Wu YB
中科院分区：
文献类型：
--
作者：
Chen SW;Zhu SQ;Pei X;Qiu BQ;Xiong D;Long X;Lin K;Lu F;Xu JJ;Wu YB
CD 8 + T细胞在先天性抗肿瘤免疫应答中起关键作用。最近，CD 8 + T细胞功能障碍已在包括非小细胞肺癌（NSCLC）在内的各种恶性肿瘤中得到证实。然而，CD 8 + T细胞功能障碍在人类NSCLC中的分子生物学机制仍不清楚。采用实时定量聚合酶链反应（qRT-PCR）检测NSCLC组织、外泌体和细胞系中环状泛素特异性蛋白酶7（circUSP 7）的表达。使用超离心法和ExoQuick Exosome沉淀溶液试剂盒从NSCLC细胞的培养基和NSCLC患者的血浆中分离外泌体。然后通过透射电子显微镜（TEM）、NanoSight和蛋白质印迹法表征外泌体。通过酶联免疫吸附试验（ELISA）评估circUSP 7在CD 8 + T细胞功能障碍中的作用。进行了体内环状RNA（circRNA）沉淀（circRIP）、RNA免疫沉淀（RIP）和荧光素酶报告基因测定，以探索circUSP 7在CD 8 + T细胞中的分子机制。在一项回顾性研究中，确定了NSCLC组织中circUSP 7的临床特征和预后意义。circUSP 7在人NSCLC组织中的表达水平高于匹配的邻近非肿瘤组织。circUSP 7水平升高表明NSCLC患者临床预后不良和CD 8 + T细胞功能障碍。在NSCLC患者血浆中发现的circUSP 7主要由NSCLC细胞以外来体方式分泌，并且circUSP 7抑制CD 8 + T细胞分泌IFN-γ、TNF-α、颗粒酶-B和穿孔蛋白。此外，circUSP 7通过海绵状miR-934上调含Src同源区2（SH 2）的蛋白酪氨酸磷酸酶2（SHP 2）的表达来抑制CD 8 + T细胞功能。最后，我们表明circUSP 7可能会促进NSCLC患者对抗PD 1免疫治疗的耐药性。外泌体circUSP 7主要由NSCLC细胞分泌，并通过促进NSCLC中的CD 8 + T细胞功能障碍而有助于免疫抑制。CircUSP 7诱导抗PD 1免疫疗法的耐药性，为NSCLC患者提供了一种潜在的治疗策略。在线版本包含补充材料，可通过10.1186/s12943-021-01448-x获得。
CD8+ T cells play a critical role in the innate antitumour immune response. Recently, CD8+ T cell dysfunction has been verified in various malignant cancers, including non-small cell lung cancer (NSCLC). However, the molecular biological mechanisms of CD8+ T cell dysfunction in human NSCLC are still unclear. The expression of circular ubiquitin-specific protease-7 (circUSP7) in NSCLC tissues, exosomes, and cell lines was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Exosomes were isolated from the culture medium of NSCLC cells and the plasma of NSCLC patients using an ultracentrifugation method and the ExoQuick Exosome Precipitation Solution kit. The exosomes were then characterized by transmission electronic microscopy (TEM), NanoSight and western blotting. The role of circUSP7 in CD8+ T cell dysfunction was assessed by enzyme-linked immunosorbent assay (ELISA). In vivo circular RNA (circRNA) precipitation (circRIP), RNA immunoprecipitation (RIP), and luciferase reporter assays were performed to explore the molecular mechanisms of circUSP7 in CD8+ T cells. In a retrospective study, the clinical characteristics and prognostic significance of circUSP7 in NSCLC tissues were determined. The expression levels of circUSP7 were higher in human NSCLC tissues than in matched adjacent nontumour tissues. Increased levels of circUSP7 indicate poor clinical prognosis and CD8+ T cell dysfunction in patients with NSCLC. The circUSP7 found in NSCLC patient plasma is predominantly secreted by NSCLC cells in an exosomal manner, and circUSP7 inhibits IFN-γ, TNF-α, Granzyme-B and Perforin secretion by CD8+ T cells. Furthermore, circUSP7 inhibits CD8+ T cell function by upregulating the expression of Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) via sponging miR-934. Finally, we show that circUSP7 may promote resistance to anti-PD1 immunotherapy in NSCLC patients. Exosomal circUSP7 is predominantly secreted by NSCLC cells and contributes to immunosuppression by promoting CD8+ T cell dysfunction in NSCLC. CircUSP7 induces resistance to anti-PD1 immunotherapy, providing a potential therapeutic strategy for NSCLC patients. The online version contains supplementary material available at 10.1186/s12943-021-01448-x.
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影响因子：
4.4
作者：
Chemnitz, JM;Parry, RV;Riley, JL
通讯作者：
Riley, JL
DOI：
10.1093/annonc/mdx765
发表时间：
2018-03-01
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Krug AK;Enderle D;Karlovich C;Priewasser T;Bentink S;Spiel A;Brinkmann K;Emenegger J;Grimm DG;Castellanos-Rizaldos E;Goldman JW;Sequist LV;Soria JC;Camidge DR;Gadgeel SM;Wakelee HA;Raponi M;Noerholm M;Skog J
通讯作者：
Skog J
exoRBase：人类血液外泌体中circRNA、lncRNA和mRNA的数据库
影响因子：
14.9
作者：
Li S;Li Y;Chen B;Zhao J;Yu S;Tang Y;Zheng Q;Li Y;Wang P;He X;Huang S
通讯作者：
Huang S
外泌体传输的 lncARSR 通过充当竞争性内源性 RNA 促进肾癌舒尼替尼耐药
影响因子：
50.3
作者：
Qu, Le;Ding, Jin;Wang, Lin-Hui
通讯作者：
Wang, Lin-Hui
影响因子：
45.3
作者：
Horn, Leora;Spigel, David R.;Eberhardt, Wilfried E. E.
通讯作者：
Eberhardt, Wilfried E. E.