Cancer cell-derived exosomal circUSP7 induces CD8+ T cell dysfunction and anti-PD1 resistance by regulating the miR-934/SHP2 axis in NSCLC

Abstract Background 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 h...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Shi-Wei Chen, Shu-Qiang Zhu, Xu Pei, Bai-Quan Qiu, Dian Xiong, Xiang Long, Kun Lin, Feng Lu, Jian-Jun Xu, Yong-Bing Wu
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	circUSP7 NSCLC Exosome Anti-PD1 miR-934 SHP2 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/730edc6b66214955b83f9e647d2a8a23
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:730edc6b66214955b83f9e647d2a8a23
record_format	dspace
spelling	oai:doaj.org-article:730edc6b66214955b83f9e647d2a8a232021-11-14T12:05:35ZCancer cell-derived exosomal circUSP7 induces CD8+ T cell dysfunction and anti-PD1 resistance by regulating the miR-934/SHP2 axis in NSCLC10.1186/s12943-021-01448-x1476-4598https://doaj.org/article/730edc6b66214955b83f9e647d2a8a232021-11-01T00:00:00Zhttps://doi.org/10.1186/s12943-021-01448-xhttps://doaj.org/toc/1476-4598Abstract Background 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. Methods 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. Results 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. Conclusions 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.Shi-Wei ChenShu-Qiang ZhuXu PeiBai-Quan QiuDian XiongXiang LongKun LinFeng LuJian-Jun XuYong-Bing WuBMCarticlecircUSP7NSCLCExosomeAnti-PD1miR-934SHP2Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENMolecular Cancer, Vol 20, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	circUSP7 NSCLC Exosome Anti-PD1 miR-934 SHP2 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	circUSP7 NSCLC Exosome Anti-PD1 miR-934 SHP2 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Shi-Wei Chen Shu-Qiang Zhu Xu Pei Bai-Quan Qiu Dian Xiong Xiang Long Kun Lin Feng Lu Jian-Jun Xu Yong-Bing Wu Cancer cell-derived exosomal circUSP7 induces CD8+ T cell dysfunction and anti-PD1 resistance by regulating the miR-934/SHP2 axis in NSCLC
description	Abstract Background 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. Methods 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. Results 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. Conclusions 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.
format	article
author	Shi-Wei Chen Shu-Qiang Zhu Xu Pei Bai-Quan Qiu Dian Xiong Xiang Long Kun Lin Feng Lu Jian-Jun Xu Yong-Bing Wu
author_facet	Shi-Wei Chen Shu-Qiang Zhu Xu Pei Bai-Quan Qiu Dian Xiong Xiang Long Kun Lin Feng Lu Jian-Jun Xu Yong-Bing Wu
author_sort	Shi-Wei Chen
title	Cancer cell-derived exosomal circUSP7 induces CD8+ T cell dysfunction and anti-PD1 resistance by regulating the miR-934/SHP2 axis in NSCLC
title_short	Cancer cell-derived exosomal circUSP7 induces CD8+ T cell dysfunction and anti-PD1 resistance by regulating the miR-934/SHP2 axis in NSCLC
title_full	Cancer cell-derived exosomal circUSP7 induces CD8+ T cell dysfunction and anti-PD1 resistance by regulating the miR-934/SHP2 axis in NSCLC
title_fullStr	Cancer cell-derived exosomal circUSP7 induces CD8+ T cell dysfunction and anti-PD1 resistance by regulating the miR-934/SHP2 axis in NSCLC
title_full_unstemmed	Cancer cell-derived exosomal circUSP7 induces CD8+ T cell dysfunction and anti-PD1 resistance by regulating the miR-934/SHP2 axis in NSCLC
title_sort	cancer cell-derived exosomal circusp7 induces cd8+ t cell dysfunction and anti-pd1 resistance by regulating the mir-934/shp2 axis in nsclc
publisher	BMC
publishDate	2021
url	https://doaj.org/article/730edc6b66214955b83f9e647d2a8a23
work_keys_str_mv	AT shiweichen cancercellderivedexosomalcircusp7inducescd8tcelldysfunctionandantipd1resistancebyregulatingthemir934shp2axisinnsclc AT shuqiangzhu cancercellderivedexosomalcircusp7inducescd8tcelldysfunctionandantipd1resistancebyregulatingthemir934shp2axisinnsclc AT xupei cancercellderivedexosomalcircusp7inducescd8tcelldysfunctionandantipd1resistancebyregulatingthemir934shp2axisinnsclc AT baiquanqiu cancercellderivedexosomalcircusp7inducescd8tcelldysfunctionandantipd1resistancebyregulatingthemir934shp2axisinnsclc AT dianxiong cancercellderivedexosomalcircusp7inducescd8tcelldysfunctionandantipd1resistancebyregulatingthemir934shp2axisinnsclc AT xianglong cancercellderivedexosomalcircusp7inducescd8tcelldysfunctionandantipd1resistancebyregulatingthemir934shp2axisinnsclc AT kunlin cancercellderivedexosomalcircusp7inducescd8tcelldysfunctionandantipd1resistancebyregulatingthemir934shp2axisinnsclc AT fenglu cancercellderivedexosomalcircusp7inducescd8tcelldysfunctionandantipd1resistancebyregulatingthemir934shp2axisinnsclc AT jianjunxu cancercellderivedexosomalcircusp7inducescd8tcelldysfunctionandantipd1resistancebyregulatingthemir934shp2axisinnsclc AT yongbingwu cancercellderivedexosomalcircusp7inducescd8tcelldysfunctionandantipd1resistancebyregulatingthemir934shp2axisinnsclc
_version_	1718429468567011328

Cancer cell-derived exosomal circUSP7 induces CD8+ T cell dysfunction and anti-PD1 resistance by regulating the miR-934/SHP2 axis in NSCLC

Ejemplares similares