Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma
The combination of atezolizumab and bevacizumab (atezo+bev) is the current standard of care for advanced hepatocellular carcinoma (HCC), providing a median overall survival (OS) of 19.2 months. Here, we aim to uncover the underlying cellular processes driving clinical benefit vs. resistance to atezo...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Idioma: | inglés |
| OAI Identifier: | oai:dnet:uabarcelona_::748b7601601a72c6320f6623ecfb4d84 |
| Acceso en línea: | https://ddd.uab.cat/record/328431 https://dx.doi.org/urn:doi:10.1016/j.jhep.2024.12.016 |
| Access Level: | acceso abierto |
| Palabra clave: | Advanced Hepatocellular Carcinoma Atezolizumab and bevacizumab Biomarkers of Response Single-Cell RNA-Sequencing Primary Resistance |
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| dc.title.none.fl_str_mv |
Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma |
| title |
Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma |
| spellingShingle |
Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma Cappuyns, Sarah Advanced Hepatocellular Carcinoma Atezolizumab and bevacizumab Biomarkers of Response Single-Cell RNA-Sequencing Primary Resistance |
| title_short |
Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma |
| title_full |
Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma |
| title_fullStr |
Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma |
| title_full_unstemmed |
Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma |
| title_sort |
Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma |
| dc.creator.none.fl_str_mv |
Cappuyns, Sarah Piqué-Gili, Marta Esteban-Fabró, Roger Philips, Gino Balaseviciute, Ugne Pinyol, Roser|||0000-0002-0288-6314 Gris-Oliver, Albert|||0000-0003-1802-9541 Vandecaveye, Vincent Abril-Fornaguera, Jordi|||0000-0002-5871-4052 Montironi, Carla|||0000-0002-1453-2193 Bassaganyas, Laia|||0000-0002-4575-0214 Peix, Judit Zeitlhoefler, Marcus Mesropian, Agavni Huguet Pradell, Júlia Haber, Philipp K Figueiredo, Igor Ioannou, Giorgio Gonzalez Kozlova, Edgar D'Alessio, Antonio Mohr, Raphael Meyer, Tim Lachenmayer, Anja|||0000-0002-5879-5737 Marquardt, Jens U Reeves, Helen L.|||0000-0003-0359-9795 Edeline, Julien Finkelmeier, Fabian Trojan, Jorg Galle, Peter R Foerster, Friedrich Mínguez Rosique, Beatriz|||0000-0002-7276-9666 Montal, Robert Gnjatic, Sacha Pinato, David James|||0000-0002-3529-0103 Heikenwälder, Mathias Verslype, Chris Van Cutsem, Eric|||0000-0002-6372-1230 Lambrechts, Diether Villanueva, Augusto|||0000-0003-3585-3727 Dekervel, Jeroen Llovet, Josep M.|||0000-0003-0547-2667 |
| author |
Cappuyns, Sarah |
| author_facet |
Cappuyns, Sarah Piqué-Gili, Marta Esteban-Fabró, Roger Philips, Gino Balaseviciute, Ugne Pinyol, Roser|||0000-0002-0288-6314 Gris-Oliver, Albert|||0000-0003-1802-9541 Vandecaveye, Vincent Abril-Fornaguera, Jordi|||0000-0002-5871-4052 Montironi, Carla|||0000-0002-1453-2193 Bassaganyas, Laia|||0000-0002-4575-0214 Peix, Judit Zeitlhoefler, Marcus Mesropian, Agavni Huguet Pradell, Júlia Haber, Philipp K Figueiredo, Igor Ioannou, Giorgio Gonzalez Kozlova, Edgar D'Alessio, Antonio Mohr, Raphael Meyer, Tim Lachenmayer, Anja|||0000-0002-5879-5737 Marquardt, Jens U Reeves, Helen L.|||0000-0003-0359-9795 Edeline, Julien Finkelmeier, Fabian Trojan, Jorg Galle, Peter R Foerster, Friedrich Mínguez Rosique, Beatriz|||0000-0002-7276-9666 Montal, Robert Gnjatic, Sacha Pinato, David James|||0000-0002-3529-0103 Heikenwälder, Mathias Verslype, Chris Van Cutsem, Eric|||0000-0002-6372-1230 Lambrechts, Diether Villanueva, Augusto|||0000-0003-3585-3727 Dekervel, Jeroen Llovet, Josep M.|||0000-0003-0547-2667 |
| author_role |
author |
| author2 |
Piqué-Gili, Marta Esteban-Fabró, Roger Philips, Gino Balaseviciute, Ugne Pinyol, Roser|||0000-0002-0288-6314 Gris-Oliver, Albert|||0000-0003-1802-9541 Vandecaveye, Vincent Abril-Fornaguera, Jordi|||0000-0002-5871-4052 Montironi, Carla|||0000-0002-1453-2193 Bassaganyas, Laia|||0000-0002-4575-0214 Peix, Judit Zeitlhoefler, Marcus Mesropian, Agavni Huguet Pradell, Júlia Haber, Philipp K Figueiredo, Igor Ioannou, Giorgio Gonzalez Kozlova, Edgar D'Alessio, Antonio Mohr, Raphael Meyer, Tim Lachenmayer, Anja|||0000-0002-5879-5737 Marquardt, Jens U Reeves, Helen L.|||0000-0003-0359-9795 Edeline, Julien Finkelmeier, Fabian Trojan, Jorg Galle, Peter R Foerster, Friedrich Mínguez Rosique, Beatriz|||0000-0002-7276-9666 Montal, Robert Gnjatic, Sacha Pinato, David James|||0000-0002-3529-0103 Heikenwälder, Mathias Verslype, Chris Van Cutsem, Eric|||0000-0002-6372-1230 Lambrechts, Diether Villanueva, Augusto|||0000-0003-3585-3727 Dekervel, Jeroen Llovet, Josep M.|||0000-0003-0547-2667 |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Advanced Hepatocellular Carcinoma Atezolizumab and bevacizumab Biomarkers of Response Single-Cell RNA-Sequencing Primary Resistance |
| topic |
Advanced Hepatocellular Carcinoma Atezolizumab and bevacizumab Biomarkers of Response Single-Cell RNA-Sequencing Primary Resistance |
| description |
The combination of atezolizumab and bevacizumab (atezo+bev) is the current standard of care for advanced hepatocellular carcinoma (HCC), providing a median overall survival (OS) of 19.2 months. Here, we aim to uncover the underlying cellular processes driving clinical benefit vs. resistance to atezo+bev. We harnessed the power of single-cell RNA sequencing in advanced HCC to derive gene expression signatures recapitulating 21 cell phenotypes. These signatures were applied to 422 RNA-sequencing samples of patients with advanced HCC treated with atezo+bev (n = 317) vs. atezolizumab (n = 47) or sorafenib (n = 58) as comparators. We unveiled two distinct patterns of response to atezo+bev. First, an immune-mediated response characterised by the combined presence of CD8+ T effector cells and pro-inflammatory CXCL10+ macrophages, representing an immune-rich microenvironment. Second, a non-immune, angiogenesis-related response distinguishable by a reduced expression of the VEGF co-receptor neuropilin-1 (NRP1), a biomarker that specifically predicts improved OS upon atezo+bev vs. sorafenib (p = 0.039). Primary resistance was associated with an enrichment of immunosuppressive myeloid populations, namely CD14+ monocytes and TREM2+ macrophages, and Notch pathway activation. Based on these mechanistic insights we define " Immune-competent " and " Angiogenesis-driven " molecular subgroups, each associated with a significantly longer OS with atezo+bev vs. sorafenib (p of interaction = 0.027), and a " Resistant" subset. Our study unveils two distinct molecular subsets of clinical benefit to atezolizumab plus bevacizumab in advanced HCC (" Immune-competent" and " Angiogenesis-driven") as well as the main traits of primary resistance to this therapy, thus providing a molecular framework to stratify patients based on clinical outcome and guiding potential strategies to overcome resistance. Atezolizumab + bevacizumab (atezo+bev) is standard of care in advanced hepatocellular carcinoma (HCC), yet molecular determinants of clinical benefit to the combination remain unclear. This study harnesses the power of single-cell RNA sequencing, deriving gene expression signatures representing 21 cell subtypes in the advanced HCC microenvironment. By applying these signatures to RNA-sequencing samples, we reveal two distinct response patterns to atezo+bev and define molecular subgroups of patients (" Immune-competent" and " Angiogenesis-driven" vs. "Resistant") with differential clinical outcomes upon treatment with atezo+bev, pointing towards the role of immunosuppressive myeloid cell types and Notch pathway activation in primary resistance to atezo+bev. These results may help refine treatment strategies and improve outcomes for patients with advanced HCC, while also guiding future research aimed at overcoming resistance mechanisms. |
| publishDate |
2025 |
| dc.date.none.fl_str_mv |
2 2025-01-01 2025 2025-01-01 |
| dc.type.none.fl_str_mv |
Article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://ddd.uab.cat/record/328431 https://dx.doi.org/urn:doi:10.1016/j.jhep.2024.12.016 |
| url |
https://ddd.uab.cat/record/328431 https://dx.doi.org/urn:doi:10.1016/j.jhep.2024.12.016 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.relation.none.fl_str_mv |
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 BES-2017-081286 Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2022-139365OB-I00 Generalitat de Catalunya https://doi.org/10.13039/501100002809 2021/SGR-00338 European Commission https://doi.org/10.13039/501100000780 101136622 Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2022-139365OB-I00 "la Caixa" Foundation https://doi.org/10.13039/100010434 LCF/PR/SP23/5295000 Generalitat de Catalunya https://doi.org/10.13039/501100002809 2021/SGR-01347 |
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open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by-nc-nd/4.0/ |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by-nc-nd/4.0/ |
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openAccess |
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application/pdf |
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reponame:Dipòsit Digital de Documents de la UAB instname:Universitat Autònoma de Barcelona |
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Universitat Autònoma de Barcelona |
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Dipòsit Digital de Documents de la UAB |
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Dipòsit Digital de Documents de la UAB |
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1869406619668840448 |
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Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinomaCappuyns, SarahPiqué-Gili, MartaEsteban-Fabró, RogerPhilips, GinoBalaseviciute, UgnePinyol, Roser|||0000-0002-0288-6314Gris-Oliver, Albert|||0000-0003-1802-9541Vandecaveye, VincentAbril-Fornaguera, Jordi|||0000-0002-5871-4052Montironi, Carla|||0000-0002-1453-2193Bassaganyas, Laia|||0000-0002-4575-0214Peix, JuditZeitlhoefler, MarcusMesropian, AgavniHuguet Pradell, JúliaHaber, Philipp KFigueiredo, IgorIoannou, GiorgioGonzalez Kozlova, EdgarD'Alessio, AntonioMohr, RaphaelMeyer, TimLachenmayer, Anja|||0000-0002-5879-5737Marquardt, Jens UReeves, Helen L.|||0000-0003-0359-9795Edeline, JulienFinkelmeier, FabianTrojan, JorgGalle, Peter RFoerster, FriedrichMínguez Rosique, Beatriz|||0000-0002-7276-9666Montal, RobertGnjatic, SachaPinato, David James|||0000-0002-3529-0103Heikenwälder, MathiasVerslype, ChrisVan Cutsem, Eric|||0000-0002-6372-1230Lambrechts, DietherVillanueva, Augusto|||0000-0003-3585-3727Dekervel, JeroenLlovet, Josep M.|||0000-0003-0547-2667Advanced Hepatocellular CarcinomaAtezolizumab and bevacizumabBiomarkers of ResponseSingle-Cell RNA-SequencingPrimary ResistanceThe combination of atezolizumab and bevacizumab (atezo+bev) is the current standard of care for advanced hepatocellular carcinoma (HCC), providing a median overall survival (OS) of 19.2 months. Here, we aim to uncover the underlying cellular processes driving clinical benefit vs. resistance to atezo+bev. We harnessed the power of single-cell RNA sequencing in advanced HCC to derive gene expression signatures recapitulating 21 cell phenotypes. These signatures were applied to 422 RNA-sequencing samples of patients with advanced HCC treated with atezo+bev (n = 317) vs. atezolizumab (n = 47) or sorafenib (n = 58) as comparators. We unveiled two distinct patterns of response to atezo+bev. First, an immune-mediated response characterised by the combined presence of CD8+ T effector cells and pro-inflammatory CXCL10+ macrophages, representing an immune-rich microenvironment. Second, a non-immune, angiogenesis-related response distinguishable by a reduced expression of the VEGF co-receptor neuropilin-1 (NRP1), a biomarker that specifically predicts improved OS upon atezo+bev vs. sorafenib (p = 0.039). Primary resistance was associated with an enrichment of immunosuppressive myeloid populations, namely CD14+ monocytes and TREM2+ macrophages, and Notch pathway activation. Based on these mechanistic insights we define " Immune-competent " and " Angiogenesis-driven " molecular subgroups, each associated with a significantly longer OS with atezo+bev vs. sorafenib (p of interaction = 0.027), and a " Resistant" subset. Our study unveils two distinct molecular subsets of clinical benefit to atezolizumab plus bevacizumab in advanced HCC (" Immune-competent" and " Angiogenesis-driven") as well as the main traits of primary resistance to this therapy, thus providing a molecular framework to stratify patients based on clinical outcome and guiding potential strategies to overcome resistance. Atezolizumab + bevacizumab (atezo+bev) is standard of care in advanced hepatocellular carcinoma (HCC), yet molecular determinants of clinical benefit to the combination remain unclear. This study harnesses the power of single-cell RNA sequencing, deriving gene expression signatures representing 21 cell subtypes in the advanced HCC microenvironment. By applying these signatures to RNA-sequencing samples, we reveal two distinct response patterns to atezo+bev and define molecular subgroups of patients (" Immune-competent" and " Angiogenesis-driven" vs. "Resistant") with differential clinical outcomes upon treatment with atezo+bev, pointing towards the role of immunosuppressive myeloid cell types and Notch pathway activation in primary resistance to atezo+bev. These results may help refine treatment strategies and improve outcomes for patients with advanced HCC, while also guiding future research aimed at overcoming resistance mechanisms. 22025-01-0120252025-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/328431https://dx.doi.org/urn:doi:10.1016/j.jhep.2024.12.016reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 BES-2017-081286Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2022-139365OB-I00Generalitat de Catalunya https://doi.org/10.13039/501100002809 2021/SGR-00338European Commission https://doi.org/10.13039/501100000780 101136622Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2022-139365OB-I00"la Caixa" Foundation https://doi.org/10.13039/100010434 LCF/PR/SP23/5295000Generalitat de Catalunya https://doi.org/10.13039/501100002809 2021/SGR-01347open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:dnet:uabarcelona_::748b7601601a72c6320f6623ecfb4d842026-06-06T12:50:31Z |
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15.811543 |