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...
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| Format: | Article |
| Language: | English |
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BMC
2021-11-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-021-01448-x |
| _version_ | 1819260793988841472 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-23T19:31:34Z |
| format | Article |
| id | doaj.art-730edc6b66214955b83f9e647d2a8a23 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-23T19:31:34Z |
| publishDate | 2021-11-01 |
| publisher | BMC |
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| series | Molecular Cancer |
| spelling | doaj.art-730edc6b66214955b83f9e647d2a8a232022-12-21T17:33:53ZengBMCMolecular Cancer1476-45982021-11-0120111810.1186/s12943-021-01448-xCancer cell-derived exosomal circUSP7 induces CD8+ T cell dysfunction and anti-PD1 resistance by regulating the miR-934/SHP2 axis in NSCLCShi-Wei Chen0Shu-Qiang Zhu1Xu Pei2Bai-Quan Qiu3Dian Xiong4Xiang Long5Kun Lin6Feng Lu7Jian-Jun Xu8Yong-Bing Wu9Department of Cardiothoracic Surgery, the Second Affiliated Hospital of Nanchang UniversityDepartment of Cardiothoracic Surgery, the Second Affiliated Hospital of Nanchang UniversityDepartment of Cardiothoracic Surgery, the Second Affiliated Hospital of Nanchang UniversityDepartment of Cardiothoracic Surgery, the Second Affiliated Hospital of Nanchang UniversityDepartment of Cardiothoracic Surgery, the Second Affiliated Hospital of Nanchang UniversityDepartment of Cardiothoracic Surgery, the Second Affiliated Hospital of Nanchang UniversityDepartment of Cardiothoracic Surgery, the Second Affiliated Hospital of Nanchang UniversityDepartment of Cardiothoracic Surgery, the Second Affiliated Hospital of Nanchang UniversityDepartment of Cardiothoracic Surgery, the Second Affiliated Hospital of Nanchang UniversityDepartment of Cardiothoracic Surgery, the Second Affiliated Hospital of Nanchang UniversityAbstract 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.https://doi.org/10.1186/s12943-021-01448-xcircUSP7NSCLCExosomeAnti-PD1miR-934SHP2 |
| spellingShingle | 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 Molecular Cancer circUSP7 NSCLC Exosome Anti-PD1 miR-934 SHP2 |
| 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_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_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_sort | cancer cell derived exosomal circusp7 induces cd8 t cell dysfunction and anti pd1 resistance by regulating the mir 934 shp2 axis in nsclc |
| topic | circUSP7 NSCLC Exosome Anti-PD1 miR-934 SHP2 |
| url | https://doi.org/10.1186/s12943-021-01448-x |
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