Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma

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dc.contributor.authorCappuyns, Sarah
dc.contributor.authorPiqué-Gili, Marta
dc.contributor.authorEsteban-Fabró, Roger
dc.contributor.authorPhilips, Gino
dc.contributor.authorBalaseviciute, Ugne
dc.contributor.authorPinyol, Roser
dc.contributor.authorGris-Oliver, Albert
dc.contributor.authorVandecaveye, Vincent
dc.contributor.authorAbril-Fornaguera, Jordi
dc.contributor.authorMontironi, Carla
dc.contributor.authorBassaganyas, Laia
dc.contributor.authorPeix, Judit
dc.contributor.authorZeitlhoefle, Marcus
dc.contributor.authorMesropian, Agavni
dc.contributor.authorHuguet-Pradell, Júlia
dc.contributor.authorHaber, Philipp K.
dc.contributor.authorFigueiredo, Igor
dc.contributor.authorIoannou, Giorgio
dc.contributor.authorGonzalez-Kozlova, Edgar
dc.contributor.authorD’Alessio, Antonio
dc.contributor.authorMohr, Raphae
dc.contributor.authorMeyer, Tim
dc.contributor.authorLachenmayer, Anja
dc.contributor.authorMarquardt, Jens U.
dc.contributor.authorReeves, Helen L.
dc.contributor.authorEdeline, Julien
dc.contributor.authorFinkelmeier, Fabian
dc.contributor.authorTrojan, Jörg
dc.contributor.authorGalle, Peter R.
dc.contributor.authorFoerster, Friedrich
dc.contributor.authorMínguez, Beatriz
dc.contributor.authorMontal Roura, Robert
dc.contributor.authorGnjatic, Sacha
dc.contributor.authorPinato, David J.
dc.contributor.authorHeikenwalder, Mathias
dc.contributor.authorVerslype, Chris
dc.contributor.authorVan Cutsem, Eric
dc.contributor.authorLambrechts, Diether
dc.contributor.authorVillanueva, Augusto
dc.contributor.authorDekervel, Jeroen
dc.contributor.authorLlovet, Josep M.
dc.date.accessioned2025-06-27T09:00:11Z
dc.date.available2025-06-27T09:00:11Z
dc.date.issued2025
dc.description.abstractBackground & 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.
dc.identifier.doihttps://doi.org/10.1016/j.jhep.2024.12.016
dc.identifier.issn0168-8278
dc.identifier.urihttps://hdl.handle.net/10459.1/468218
dc.language.isoeng
dc.publisherElsevier
dc.relation.isformatofReproducció del document publicat a https://doi.org/10.1016/j.jhep.2024.12.016
dc.relation.ispartofJournal of Hepatology, 2025, vol. 82, núm. 6, p. 1036-1049
dc.rightscc-by-nc-nd (c) Sarah Cappuyns et al., 2025
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectAdvanced Hepatocellular Carcinoma
dc.subjectAtezolizumab and bevacizumab
dc.subjectBiomarkers of Response
dc.titleSingle-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
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