Overexpression of transposable elements is associated with immune evasion and poor outcome in colorectal cancer
High immune cell infiltration of the tumour microenvironment is generally associated with a good prognosis in solid cancers. However, a subset of patients with colorectal cancer (CRC) tumours with high immune cell infiltration have a poor outcome. These tumours have a high level of T cell infiltrati...
Gespeichert in:
| Veröffentlicht in: | European journal of cancer (1990) 2021-11, Vol.157, p.94-107 |
|---|---|
| Hauptverfasser: | , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 107 |
|---|---|
| container_issue | |
| container_start_page | 94 |
| container_title | European journal of cancer (1990) |
| container_volume | 157 |
| creator | Zhu, Xiaoqiang Fang, Hu Gladysz, Kornelia Barbour, Jayne A. Wong, Jason W.H. |
| description | High immune cell infiltration of the tumour microenvironment is generally associated with a good prognosis in solid cancers. However, a subset of patients with colorectal cancer (CRC) tumours with high immune cell infiltration have a poor outcome. These tumours have a high level of T cell infiltration and are also characterised by increased expression of programmed death-ligand 1 (PD-L1). As these tumours comprise both microsatellite instability and microsatellite stable subtypes, the mechanism underlying this phenotype is unknown.
Using RNA-seq data from The Cancer Genome Atlas, we quantified transposable element (TE) expression and developed a TE expression score that is predictive of prognosis and immune infiltration independent of microsatellite instability status and tumour staging in CRC.
Tumours with the highest TE expression score showed increased immune cell infiltration with upregulation of interferon (IFN) signalling pathways and downstream activation of IFN-simulated genes. As expected, cell lines treated with DNA methyltransferase inhibitor mimicked patient tumours with increased TE expression and IFN signalling. However, surprisingly, unlike high TE expressing CRC, there is little evidence for the activation of JAK-STAT signalling and PD-L1 expression in DNA methyltransferase inhibitor-treated cells. Single-cell RNA-seq analysis of CRC samples showed that PD-L1 expression is mainly confined to tumour-associated macrophages and T cells, suggesting that TE mediated IFN signalling is triggering expression of PD-L1 in immune cells rather than in tumour cells.
Our study uncovers a novel mechanism of TE driven immune evasion and highlights TE expression as an important factor for patient prognosis in CRC.
•Transposable element (TE) expression predicts survival in patients with colorectal cancer.•TE expression is associated with immune cell infiltration independent of microsatellite instability status.•TE overexpression drives programmed death-ligand 1 expression in immune cells leading to immune evasion.•A TE expression score can be used to subtype of patients with colorectal cancer. |
| doi_str_mv | 10.1016/j.ejca.2021.08.003 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2570371099</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0959804921005153</els_id><sourcerecordid>2570371099</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3203-a1727232277cebb611cfe53fc21b832af1354539371b508facbc0bcea989573</originalsourceid><addsrcrecordid>eNp9kU1v1DAQhi0EUpfCH-jJEhcuScf2Zm1LXFDFl1Sph3K3HO9EdZTYwZMs8O_rZTlx4DSX5xnNvC9jNwJaAeJwO7Y4Bt9KkKIF0wKoF2wnjLYNmE6-ZDuwnW0M7O0Ve000AoA2e9ix_HDCgr-WgkQxJ54HvhafaMnk-wk5TjhjWolH4p4oh-hXPPKfcX3icZ63VJGT_6P6dORLzoXnbQ15Rh4TD3nKBcPqJx58CljesFeDnwjf_p3X7PHzp-93X5v7hy_f7j7eN0FJUI0XWmqppNQ6YN8fhAgDdmoIUvRGST8I1e07ZZUWfQdm8KEP0Af01thOq2v2_rJ1KfnHhrS6OVLAafIJ80ZOdhqqCtZW9N0_6Ji3kuptTh5A6pqTUpWSFyqUTFRwcEuJsy-_nQB3bsCN7tyAOzfgwLjaQJU-XCSsj54iFkchYk3hGM-ZuGOO_9OfAauVkE0</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2602707833</pqid></control><display><type>article</type><title>Overexpression of transposable elements is associated with immune evasion and poor outcome in colorectal cancer</title><source>Elsevier ScienceDirect Journals</source><creator>Zhu, Xiaoqiang ; Fang, Hu ; Gladysz, Kornelia ; Barbour, Jayne A. ; Wong, Jason W.H.</creator><creatorcontrib>Zhu, Xiaoqiang ; Fang, Hu ; Gladysz, Kornelia ; Barbour, Jayne A. ; Wong, Jason W.H.</creatorcontrib><description>High immune cell infiltration of the tumour microenvironment is generally associated with a good prognosis in solid cancers. However, a subset of patients with colorectal cancer (CRC) tumours with high immune cell infiltration have a poor outcome. These tumours have a high level of T cell infiltration and are also characterised by increased expression of programmed death-ligand 1 (PD-L1). As these tumours comprise both microsatellite instability and microsatellite stable subtypes, the mechanism underlying this phenotype is unknown.
Using RNA-seq data from The Cancer Genome Atlas, we quantified transposable element (TE) expression and developed a TE expression score that is predictive of prognosis and immune infiltration independent of microsatellite instability status and tumour staging in CRC.
Tumours with the highest TE expression score showed increased immune cell infiltration with upregulation of interferon (IFN) signalling pathways and downstream activation of IFN-simulated genes. As expected, cell lines treated with DNA methyltransferase inhibitor mimicked patient tumours with increased TE expression and IFN signalling. However, surprisingly, unlike high TE expressing CRC, there is little evidence for the activation of JAK-STAT signalling and PD-L1 expression in DNA methyltransferase inhibitor-treated cells. Single-cell RNA-seq analysis of CRC samples showed that PD-L1 expression is mainly confined to tumour-associated macrophages and T cells, suggesting that TE mediated IFN signalling is triggering expression of PD-L1 in immune cells rather than in tumour cells.
Our study uncovers a novel mechanism of TE driven immune evasion and highlights TE expression as an important factor for patient prognosis in CRC.
•Transposable element (TE) expression predicts survival in patients with colorectal cancer.•TE expression is associated with immune cell infiltration independent of microsatellite instability status.•TE overexpression drives programmed death-ligand 1 expression in immune cells leading to immune evasion.•A TE expression score can be used to subtype of patients with colorectal cancer.</description><identifier>ISSN: 0959-8049</identifier><identifier>EISSN: 1879-0852</identifier><identifier>DOI: 10.1016/j.ejca.2021.08.003</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Apoptosis ; Cancer ; Colorectal cancer ; Colorectal carcinoma ; Deoxyribonucleic acid ; DNA ; DNA methyltransferase ; Gene expression ; Genomes ; Immune checkpoint ; Immune evasion ; Immune system ; Infiltration ; Inhibitors ; Interferon ; Lymphocytes ; Lymphocytes T ; Macrophages ; Metastases ; Microenvironments ; Microsatellite instability ; PD-L1 protein ; Phenotypes ; Prognosis ; Ribonucleic acid ; RNA ; Signal transduction ; Signaling ; Transcription activation ; Transposable elements ; Transposons ; Tumor microenvironment ; Tumors</subject><ispartof>European journal of cancer (1990), 2021-11, Vol.157, p.94-107</ispartof><rights>2021 Elsevier Ltd</rights><rights>Copyright Elsevier Science Ltd. Nov 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3203-a1727232277cebb611cfe53fc21b832af1354539371b508facbc0bcea989573</citedby><cites>FETCH-LOGICAL-c3203-a1727232277cebb611cfe53fc21b832af1354539371b508facbc0bcea989573</cites><orcidid>0000-0003-3587-7788 ; 0000-0003-2953-7728</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0959804921005153$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids></links><search><creatorcontrib>Zhu, Xiaoqiang</creatorcontrib><creatorcontrib>Fang, Hu</creatorcontrib><creatorcontrib>Gladysz, Kornelia</creatorcontrib><creatorcontrib>Barbour, Jayne A.</creatorcontrib><creatorcontrib>Wong, Jason W.H.</creatorcontrib><title>Overexpression of transposable elements is associated with immune evasion and poor outcome in colorectal cancer</title><title>European journal of cancer (1990)</title><description>High immune cell infiltration of the tumour microenvironment is generally associated with a good prognosis in solid cancers. However, a subset of patients with colorectal cancer (CRC) tumours with high immune cell infiltration have a poor outcome. These tumours have a high level of T cell infiltration and are also characterised by increased expression of programmed death-ligand 1 (PD-L1). As these tumours comprise both microsatellite instability and microsatellite stable subtypes, the mechanism underlying this phenotype is unknown.
Using RNA-seq data from The Cancer Genome Atlas, we quantified transposable element (TE) expression and developed a TE expression score that is predictive of prognosis and immune infiltration independent of microsatellite instability status and tumour staging in CRC.
Tumours with the highest TE expression score showed increased immune cell infiltration with upregulation of interferon (IFN) signalling pathways and downstream activation of IFN-simulated genes. As expected, cell lines treated with DNA methyltransferase inhibitor mimicked patient tumours with increased TE expression and IFN signalling. However, surprisingly, unlike high TE expressing CRC, there is little evidence for the activation of JAK-STAT signalling and PD-L1 expression in DNA methyltransferase inhibitor-treated cells. Single-cell RNA-seq analysis of CRC samples showed that PD-L1 expression is mainly confined to tumour-associated macrophages and T cells, suggesting that TE mediated IFN signalling is triggering expression of PD-L1 in immune cells rather than in tumour cells.
Our study uncovers a novel mechanism of TE driven immune evasion and highlights TE expression as an important factor for patient prognosis in CRC.
•Transposable element (TE) expression predicts survival in patients with colorectal cancer.•TE expression is associated with immune cell infiltration independent of microsatellite instability status.•TE overexpression drives programmed death-ligand 1 expression in immune cells leading to immune evasion.•A TE expression score can be used to subtype of patients with colorectal cancer.</description><subject>Apoptosis</subject><subject>Cancer</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA methyltransferase</subject><subject>Gene expression</subject><subject>Genomes</subject><subject>Immune checkpoint</subject><subject>Immune evasion</subject><subject>Immune system</subject><subject>Infiltration</subject><subject>Inhibitors</subject><subject>Interferon</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Macrophages</subject><subject>Metastases</subject><subject>Microenvironments</subject><subject>Microsatellite instability</subject><subject>PD-L1 protein</subject><subject>Phenotypes</subject><subject>Prognosis</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Transcription activation</subject><subject>Transposable elements</subject><subject>Transposons</subject><subject>Tumor microenvironment</subject><subject>Tumors</subject><issn>0959-8049</issn><issn>1879-0852</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kU1v1DAQhi0EUpfCH-jJEhcuScf2Zm1LXFDFl1Sph3K3HO9EdZTYwZMs8O_rZTlx4DSX5xnNvC9jNwJaAeJwO7Y4Bt9KkKIF0wKoF2wnjLYNmE6-ZDuwnW0M7O0Ve000AoA2e9ix_HDCgr-WgkQxJ54HvhafaMnk-wk5TjhjWolH4p4oh-hXPPKfcX3icZ63VJGT_6P6dORLzoXnbQ15Rh4TD3nKBcPqJx58CljesFeDnwjf_p3X7PHzp-93X5v7hy_f7j7eN0FJUI0XWmqppNQ6YN8fhAgDdmoIUvRGST8I1e07ZZUWfQdm8KEP0Af01thOq2v2_rJ1KfnHhrS6OVLAafIJ80ZOdhqqCtZW9N0_6Ji3kuptTh5A6pqTUpWSFyqUTFRwcEuJsy-_nQB3bsCN7tyAOzfgwLjaQJU-XCSsj54iFkchYk3hGM-ZuGOO_9OfAauVkE0</recordid><startdate>202111</startdate><enddate>202111</enddate><creator>Zhu, Xiaoqiang</creator><creator>Fang, Hu</creator><creator>Gladysz, Kornelia</creator><creator>Barbour, Jayne A.</creator><creator>Wong, Jason W.H.</creator><general>Elsevier Ltd</general><general>Elsevier Science Ltd</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7TO</scope><scope>7U7</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-3587-7788</orcidid><orcidid>https://orcid.org/0000-0003-2953-7728</orcidid></search><sort><creationdate>202111</creationdate><title>Overexpression of transposable elements is associated with immune evasion and poor outcome in colorectal cancer</title><author>Zhu, Xiaoqiang ; Fang, Hu ; Gladysz, Kornelia ; Barbour, Jayne A. ; Wong, Jason W.H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3203-a1727232277cebb611cfe53fc21b832af1354539371b508facbc0bcea989573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Apoptosis</topic><topic>Cancer</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA methyltransferase</topic><topic>Gene expression</topic><topic>Genomes</topic><topic>Immune checkpoint</topic><topic>Immune evasion</topic><topic>Immune system</topic><topic>Infiltration</topic><topic>Inhibitors</topic><topic>Interferon</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Macrophages</topic><topic>Metastases</topic><topic>Microenvironments</topic><topic>Microsatellite instability</topic><topic>PD-L1 protein</topic><topic>Phenotypes</topic><topic>Prognosis</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>Transcription activation</topic><topic>Transposable elements</topic><topic>Transposons</topic><topic>Tumor microenvironment</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhu, Xiaoqiang</creatorcontrib><creatorcontrib>Fang, Hu</creatorcontrib><creatorcontrib>Gladysz, Kornelia</creatorcontrib><creatorcontrib>Barbour, Jayne A.</creatorcontrib><creatorcontrib>Wong, Jason W.H.</creatorcontrib><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of cancer (1990)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhu, Xiaoqiang</au><au>Fang, Hu</au><au>Gladysz, Kornelia</au><au>Barbour, Jayne A.</au><au>Wong, Jason W.H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Overexpression of transposable elements is associated with immune evasion and poor outcome in colorectal cancer</atitle><jtitle>European journal of cancer (1990)</jtitle><date>2021-11</date><risdate>2021</risdate><volume>157</volume><spage>94</spage><epage>107</epage><pages>94-107</pages><issn>0959-8049</issn><eissn>1879-0852</eissn><abstract>High immune cell infiltration of the tumour microenvironment is generally associated with a good prognosis in solid cancers. However, a subset of patients with colorectal cancer (CRC) tumours with high immune cell infiltration have a poor outcome. These tumours have a high level of T cell infiltration and are also characterised by increased expression of programmed death-ligand 1 (PD-L1). As these tumours comprise both microsatellite instability and microsatellite stable subtypes, the mechanism underlying this phenotype is unknown.
Using RNA-seq data from The Cancer Genome Atlas, we quantified transposable element (TE) expression and developed a TE expression score that is predictive of prognosis and immune infiltration independent of microsatellite instability status and tumour staging in CRC.
Tumours with the highest TE expression score showed increased immune cell infiltration with upregulation of interferon (IFN) signalling pathways and downstream activation of IFN-simulated genes. As expected, cell lines treated with DNA methyltransferase inhibitor mimicked patient tumours with increased TE expression and IFN signalling. However, surprisingly, unlike high TE expressing CRC, there is little evidence for the activation of JAK-STAT signalling and PD-L1 expression in DNA methyltransferase inhibitor-treated cells. Single-cell RNA-seq analysis of CRC samples showed that PD-L1 expression is mainly confined to tumour-associated macrophages and T cells, suggesting that TE mediated IFN signalling is triggering expression of PD-L1 in immune cells rather than in tumour cells.
Our study uncovers a novel mechanism of TE driven immune evasion and highlights TE expression as an important factor for patient prognosis in CRC.
•Transposable element (TE) expression predicts survival in patients with colorectal cancer.•TE expression is associated with immune cell infiltration independent of microsatellite instability status.•TE overexpression drives programmed death-ligand 1 expression in immune cells leading to immune evasion.•A TE expression score can be used to subtype of patients with colorectal cancer.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><doi>10.1016/j.ejca.2021.08.003</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-3587-7788</orcidid><orcidid>https://orcid.org/0000-0003-2953-7728</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0959-8049 |
| ispartof | European journal of cancer (1990), 2021-11, Vol.157, p.94-107 |
| issn | 0959-8049 1879-0852 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2570371099 |
| source | Elsevier ScienceDirect Journals |
| subjects | Apoptosis Cancer Colorectal cancer Colorectal carcinoma Deoxyribonucleic acid DNA DNA methyltransferase Gene expression Genomes Immune checkpoint Immune evasion Immune system Infiltration Inhibitors Interferon Lymphocytes Lymphocytes T Macrophages Metastases Microenvironments Microsatellite instability PD-L1 protein Phenotypes Prognosis Ribonucleic acid RNA Signal transduction Signaling Transcription activation Transposable elements Transposons Tumor microenvironment Tumors |
| title | Overexpression of transposable elements is associated with immune evasion and poor outcome in colorectal cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-24T01%3A42%3A48IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Overexpression%20of%20transposable%20elements%20is%20associated%20with%20immune%20evasion%20and%20poor%20outcome%20in%20colorectal%20cancer&rft.jtitle=European%20journal%20of%20cancer%20(1990)&rft.au=Zhu,%20Xiaoqiang&rft.date=2021-11&rft.volume=157&rft.spage=94&rft.epage=107&rft.pages=94-107&rft.issn=0959-8049&rft.eissn=1879-0852&rft_id=info:doi/10.1016/j.ejca.2021.08.003&rft_dat=%3Cproquest_cross%3E2570371099%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2602707833&rft_id=info:pmid/&rft_els_id=S0959804921005153&rfr_iscdi=true |