Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma
Background & Aims 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 v...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:10459.1/468218 |
| Acceso en línea: | https://doi.org/10.1016/j.jhep.2024.12.016 https://hdl.handle.net/10459.1/468218 |
| Access Level: | acceso abierto |
| Palabra clave: | Advanced Hepatocellular Carcinoma Atezolizumab and bevacizumab Biomarkers of Response |
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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, RoserGris-Oliver, AlbertVandecaveye, VincentAbril-Fornaguera, JordiMontironi, CarlaBassaganyas, LaiaPeix, JuditZeitlhoefle, MarcusMesropian, AgavniHuguet-Pradell, JúliaHaber, Philipp K.Figueiredo, IgorIoannou, GiorgioGonzalez-Kozlova, EdgarD’Alessio, AntonioMohr, RaphaeMeyer, TimLachenmayer, AnjaMarquardt, Jens U.Reeves, Helen L.Edeline, JulienFinkelmeier, FabianTrojan, JörgGalle, Peter R.Foerster, FriedrichMínguez, BeatrizMontal Roura, RobertGnjatic, SachaPinato, David J.Heikenwalder, MathiasVerslype, ChrisVan Cutsem, EricLambrechts, DietherVillanueva, AugustoDekervel, JeroenLlovet, Josep M.Advanced Hepatocellular CarcinomaAtezolizumab and bevacizumabBiomarkers of ResponseBackground & Aims 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. Methods 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. Results 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. Conclusion 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.Elsevier2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://doi.org/10.1016/j.jhep.2024.12.016https://hdl.handle.net/10459.1/468218reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a https://doi.org/10.1016/j.jhep.2024.12.016Journal of Hepatology, 2025, vol. 82, núm. 6, p. 1036-1049cc-by-nc-nd (c) Sarah Cappuyns et al., 2025Attribution-NonCommercial-NoDerivatives 4.0 Internationalinfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-nd/4.0/oai:recercat.cat:10459.1/4682182026-05-29T05:05:01Z |
| 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 |
| 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 Gris-Oliver, Albert Vandecaveye, Vincent Abril-Fornaguera, Jordi Montironi, Carla Bassaganyas, Laia Peix, Judit Zeitlhoefle, Marcus Mesropian, Agavni Huguet-Pradell, Júlia Haber, Philipp K. Figueiredo, Igor Ioannou, Giorgio Gonzalez-Kozlova, Edgar D’Alessio, Antonio Mohr, Raphae Meyer, Tim Lachenmayer, Anja Marquardt, Jens U. Reeves, Helen L. Edeline, Julien Finkelmeier, Fabian Trojan, Jörg Galle, Peter R. Foerster, Friedrich Mínguez, Beatriz Montal Roura, Robert Gnjatic, Sacha Pinato, David J. Heikenwalder, Mathias Verslype, Chris Van Cutsem, Eric Lambrechts, Diether Villanueva, Augusto Dekervel, Jeroen Llovet, Josep M. |
| author |
Cappuyns, Sarah |
| author_facet |
Cappuyns, Sarah Piqué-Gili, Marta Esteban-Fabró, Roger Philips, Gino Balaseviciute, Ugne Pinyol, Roser Gris-Oliver, Albert Vandecaveye, Vincent Abril-Fornaguera, Jordi Montironi, Carla Bassaganyas, Laia Peix, Judit Zeitlhoefle, Marcus Mesropian, Agavni Huguet-Pradell, Júlia Haber, Philipp K. Figueiredo, Igor Ioannou, Giorgio Gonzalez-Kozlova, Edgar D’Alessio, Antonio Mohr, Raphae Meyer, Tim Lachenmayer, Anja Marquardt, Jens U. Reeves, Helen L. Edeline, Julien Finkelmeier, Fabian Trojan, Jörg Galle, Peter R. Foerster, Friedrich Mínguez, Beatriz Montal Roura, Robert Gnjatic, Sacha Pinato, David J. Heikenwalder, Mathias Verslype, Chris Van Cutsem, Eric Lambrechts, Diether Villanueva, Augusto Dekervel, Jeroen Llovet, Josep M. |
| author_role |
author |
| author2 |
Piqué-Gili, Marta Esteban-Fabró, Roger Philips, Gino Balaseviciute, Ugne Pinyol, Roser Gris-Oliver, Albert Vandecaveye, Vincent Abril-Fornaguera, Jordi Montironi, Carla Bassaganyas, Laia Peix, Judit Zeitlhoefle, Marcus Mesropian, Agavni Huguet-Pradell, Júlia Haber, Philipp K. Figueiredo, Igor Ioannou, Giorgio Gonzalez-Kozlova, Edgar D’Alessio, Antonio Mohr, Raphae Meyer, Tim Lachenmayer, Anja Marquardt, Jens U. Reeves, Helen L. Edeline, Julien Finkelmeier, Fabian Trojan, Jörg Galle, Peter R. Foerster, Friedrich Mínguez, Beatriz Montal Roura, Robert Gnjatic, Sacha Pinato, David J. Heikenwalder, Mathias Verslype, Chris Van Cutsem, Eric Lambrechts, Diether Villanueva, Augusto Dekervel, Jeroen Llovet, Josep M. |
| 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 |
| topic |
Advanced Hepatocellular Carcinoma Atezolizumab and bevacizumab Biomarkers of Response |
| description |
Background & Aims 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. Methods 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. Results 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. Conclusion 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. |
| publishDate |
2025 |
| dc.date.none.fl_str_mv |
2025 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
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https://doi.org/10.1016/j.jhep.2024.12.016 https://hdl.handle.net/10459.1/468218 |
| url |
https://doi.org/10.1016/j.jhep.2024.12.016 https://hdl.handle.net/10459.1/468218 |
| dc.language.none.fl_str_mv |
Inglés |
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Inglés |
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Reproducció del document publicat a https://doi.org/10.1016/j.jhep.2024.12.016 Journal of Hepatology, 2025, vol. 82, núm. 6, p. 1036-1049 |
| dc.rights.none.fl_str_mv |
cc-by-nc-nd (c) Sarah Cappuyns et al., 2025 Attribution-NonCommercial-NoDerivatives 4.0 International info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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cc-by-nc-nd (c) Sarah Cappuyns et al., 2025 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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openAccess |
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Elsevier |
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Elsevier |
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reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Recercat. Dipósit de la Recerca de Catalunya |
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