Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma
The accrual of myeloid-derived suppressor cells (MDSCs) represents a major obstacle to effective immunotherapy in cancer patients, but the mechanisms underlying this process in the human setting remain elusive. Here, we describe a set of microRNAs (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-1...
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| Veröffentlicht in: | The Journal of clinical investigation 2018-12, Vol.128 (12), p.5505-5516 |
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| creator | Huber, Veronica Vallacchi, Viviana Fleming, Viktor Hu, Xiaoying Cova, Agata Dugo, Matteo Shahaj, Eriomina Sulsenti, Roberta Vergani, Elisabetta Filipazzi, Paola De Laurentiis, Angela Lalli, Luca Di Guardo, Lorenza Patuzzo, Roberto Vergani, Barbara Casiraghi, Elena Cossa, Mara Gualeni, Ambra Bollati, Valentina Arienti, Flavio De Braud, Filippo Mariani, Luigi Villa, Antonello Altevogt, Peter Umansky, Viktor Rodolfo, Monica Rivoltini, Licia |
| description | The accrual of myeloid-derived suppressor cells (MDSCs) represents a major obstacle to effective immunotherapy in cancer patients, but the mechanisms underlying this process in the human setting remain elusive. Here, we describe a set of microRNAs (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, miR-99b) that are associated with MDSCs and resistance to treatment with immune checkpoint inhibitors in melanoma patients. The miRs were identified by transcriptional analyses as being responsible for the conversion of monocytes into MDSCs (CD14+HLA-DRneg cells) mediated by melanoma extracellular vesicles (EVs) and were shown to recreate MDSC features upon transfection. In melanoma patients, these miRs were increased in circulating CD14+ monocytes, plasma, and tumor samples, where they correlated with the myeloid cell infiltrate. In plasma, their baseline levels clustered with the clinical efficacy of CTLA-4 or programmed cell death protein 1 (PD-1) blockade. Hence, MDSC-related miRs represent an indicator of MDSC activity in cancer patients and a potential blood marker of a poor immunotherapy outcome. |
| doi_str_mv | 10.1172/JCI98060 |
| format | Article |
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Here, we describe a set of microRNAs (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, miR-99b) that are associated with MDSCs and resistance to treatment with immune checkpoint inhibitors in melanoma patients. The miRs were identified by transcriptional analyses as being responsible for the conversion of monocytes into MDSCs (CD14+HLA-DRneg cells) mediated by melanoma extracellular vesicles (EVs) and were shown to recreate MDSC features upon transfection. In melanoma patients, these miRs were increased in circulating CD14+ monocytes, plasma, and tumor samples, where they correlated with the myeloid cell infiltrate. In plasma, their baseline levels clustered with the clinical efficacy of CTLA-4 or programmed cell death protein 1 (PD-1) blockade. Hence, MDSC-related miRs represent an indicator of MDSC activity in cancer patients and a potential blood marker of a poor immunotherapy outcome.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI98060</identifier><identifier>PMID: 30260323</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Analysis ; Angiogenesis ; Apoptosis ; Biomedical research ; Cancer ; Cancer patients ; Cancer treatment ; Care and treatment ; CD14 antigen ; Cell death ; Cell growth ; CTLA-4 protein ; Genomes ; Genomics ; Genotype & phenotype ; Granulocytes ; Histocompatibility antigen HLA ; Immune checkpoint inhibitors ; Immunotherapy ; Infection ; Lymphocytes ; Medical prognosis ; Melanoma ; MicroRNA ; MicroRNAs ; miRNA ; Monocytes ; Patients ; PD-1 protein ; Proteins ; Skin cancer ; Suppressor cells ; Transcription ; Transfection ; Treatment outcome ; Tumors</subject><ispartof>The Journal of clinical investigation, 2018-12, Vol.128 (12), p.5505-5516</ispartof><rights>COPYRIGHT 2018 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Dec 2018</rights><rights>Copyright © 2018, American Society for Clinical Investigation 2018 American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c643t-957a725b5f5bc9ef10638ea23763bf1ba2446a5254960542c0e476a5d49dd5ba3</citedby><cites>FETCH-LOGICAL-c643t-957a725b5f5bc9ef10638ea23763bf1ba2446a5254960542c0e476a5d49dd5ba3</cites><orcidid>0000-0003-2024-7572 ; 0000-0002-9196-0298 ; 0000-0002-3820-8072 ; 0000-0002-7297-319X ; 0000-0002-8718-1005 ; 0000-0001-9360-6383 ; 0000-0002-2247-056X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264733/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264733/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30260323$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huber, Veronica</creatorcontrib><creatorcontrib>Vallacchi, Viviana</creatorcontrib><creatorcontrib>Fleming, Viktor</creatorcontrib><creatorcontrib>Hu, Xiaoying</creatorcontrib><creatorcontrib>Cova, Agata</creatorcontrib><creatorcontrib>Dugo, Matteo</creatorcontrib><creatorcontrib>Shahaj, Eriomina</creatorcontrib><creatorcontrib>Sulsenti, Roberta</creatorcontrib><creatorcontrib>Vergani, Elisabetta</creatorcontrib><creatorcontrib>Filipazzi, Paola</creatorcontrib><creatorcontrib>De Laurentiis, Angela</creatorcontrib><creatorcontrib>Lalli, Luca</creatorcontrib><creatorcontrib>Di Guardo, Lorenza</creatorcontrib><creatorcontrib>Patuzzo, Roberto</creatorcontrib><creatorcontrib>Vergani, Barbara</creatorcontrib><creatorcontrib>Casiraghi, Elena</creatorcontrib><creatorcontrib>Cossa, Mara</creatorcontrib><creatorcontrib>Gualeni, Ambra</creatorcontrib><creatorcontrib>Bollati, Valentina</creatorcontrib><creatorcontrib>Arienti, Flavio</creatorcontrib><creatorcontrib>De Braud, Filippo</creatorcontrib><creatorcontrib>Mariani, Luigi</creatorcontrib><creatorcontrib>Villa, Antonello</creatorcontrib><creatorcontrib>Altevogt, Peter</creatorcontrib><creatorcontrib>Umansky, Viktor</creatorcontrib><creatorcontrib>Rodolfo, Monica</creatorcontrib><creatorcontrib>Rivoltini, Licia</creatorcontrib><title>Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>The accrual of myeloid-derived suppressor cells (MDSCs) represents a major obstacle to effective immunotherapy in cancer patients, but the mechanisms underlying this process in the human setting remain elusive. Here, we describe a set of microRNAs (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, miR-99b) that are associated with MDSCs and resistance to treatment with immune checkpoint inhibitors in melanoma patients. The miRs were identified by transcriptional analyses as being responsible for the conversion of monocytes into MDSCs (CD14+HLA-DRneg cells) mediated by melanoma extracellular vesicles (EVs) and were shown to recreate MDSC features upon transfection. In melanoma patients, these miRs were increased in circulating CD14+ monocytes, plasma, and tumor samples, where they correlated with the myeloid cell infiltrate. In plasma, their baseline levels clustered with the clinical efficacy of CTLA-4 or programmed cell death protein 1 (PD-1) blockade. Hence, MDSC-related miRs represent an indicator of MDSC activity in cancer patients and a potential blood marker of a poor immunotherapy outcome.</description><subject>Analysis</subject><subject>Angiogenesis</subject><subject>Apoptosis</subject><subject>Biomedical research</subject><subject>Cancer</subject><subject>Cancer patients</subject><subject>Cancer treatment</subject><subject>Care and treatment</subject><subject>CD14 antigen</subject><subject>Cell death</subject><subject>Cell growth</subject><subject>CTLA-4 protein</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Genotype & phenotype</subject><subject>Granulocytes</subject><subject>Histocompatibility antigen HLA</subject><subject>Immune checkpoint inhibitors</subject><subject>Immunotherapy</subject><subject>Infection</subject><subject>Lymphocytes</subject><subject>Medical prognosis</subject><subject>Melanoma</subject><subject>MicroRNA</subject><subject>MicroRNAs</subject><subject>miRNA</subject><subject>Monocytes</subject><subject>Patients</subject><subject>PD-1 protein</subject><subject>Proteins</subject><subject>Skin cancer</subject><subject>Suppressor cells</subject><subject>Transcription</subject><subject>Transfection</subject><subject>Treatment 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Here, we describe a set of microRNAs (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, miR-99b) that are associated with MDSCs and resistance to treatment with immune checkpoint inhibitors in melanoma patients. The miRs were identified by transcriptional analyses as being responsible for the conversion of monocytes into MDSCs (CD14+HLA-DRneg cells) mediated by melanoma extracellular vesicles (EVs) and were shown to recreate MDSC features upon transfection. In melanoma patients, these miRs were increased in circulating CD14+ monocytes, plasma, and tumor samples, where they correlated with the myeloid cell infiltrate. In plasma, their baseline levels clustered with the clinical efficacy of CTLA-4 or programmed cell death protein 1 (PD-1) blockade. 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| fulltext | fulltext |
| identifier | ISSN: 0021-9738 |
| ispartof | The Journal of clinical investigation, 2018-12, Vol.128 (12), p.5505-5516 |
| issn | 0021-9738 1558-8238 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6264733 |
| source | Journals@Ovid Complete; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Analysis Angiogenesis Apoptosis Biomedical research Cancer Cancer patients Cancer treatment Care and treatment CD14 antigen Cell death Cell growth CTLA-4 protein Genomes Genomics Genotype & phenotype Granulocytes Histocompatibility antigen HLA Immune checkpoint inhibitors Immunotherapy Infection Lymphocytes Medical prognosis Melanoma MicroRNA MicroRNAs miRNA Monocytes Patients PD-1 protein Proteins Skin cancer Suppressor cells Transcription Transfection Treatment outcome Tumors |
| title | Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-02T01%3A01%3A01IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Tumor-derived%20microRNAs%20induce%20myeloid%20suppressor%20cells%20and%20predict%20immunotherapy%20resistance%20in%20melanoma&rft.jtitle=The%20Journal%20of%20clinical%20investigation&rft.au=Huber,%20Veronica&rft.date=2018-12-01&rft.volume=128&rft.issue=12&rft.spage=5505&rft.epage=5516&rft.pages=5505-5516&rft.issn=0021-9738&rft.eissn=1558-8238&rft_id=info:doi/10.1172/JCI98060&rft_dat=%3Cgale_pubme%3EA564465276%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2155898450&rft_id=info:pmid/30260323&rft_galeid=A564465276&rfr_iscdi=true |