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SC was supported by a strategic basic research fellowship from Research Foundation- Flanders (FWO; 1S95221N) and a post-doctoral fellowship from the Belgian American Educational Foundation (BAEF) . MPG was supported by a pre doctoral grant from the Spanish National Health Institute (MICINN, PRE2020-094716) and a mobility grant from "Fundacio Universitaria Agusti Pedro Pons". REF was supported by a predoctoral grant from the Spanish National Health Institute (MCINN; BES-2017-081286) and a mobility grant from "Fundacio Universitaria Agusti Pedro i Pons". UB was supported by the EILF-EASL Juan Rodes PhD Studentship from the European Association for the Study of the Liver (EASL) and the EASL International Liver Foundation (EILF) . RP is supported by the Fundacio de Recerca Clinic Barcelona-IDIBAPS and by a grant from the Spanish National Health Institute (MICINN, PID2022-139365OB-I00, funded by MICIU/AEI/10.13039/501100011033 and FEDER) . JAF was supported by a doctoral training grant from the University of Barcelona (PREDOCS-UB 2020) and by the "Societat Catalana de Digestologia" mobility grant. JP was supported by a PERIS ICT-Suport grant from the "Departament de Salut de la Generalitat de Catalunya" (SLT017/20/000206) . AM was supported by the Generalitat de Catalunya with FI-SDUR fellowship (2021 FISDU 00338) from AGAUR. JHP was supported by the predoctoral grant "Ayudas para la Formacion de Profesorado Universitario (FPU) " (FPU21/03361) and a mobility grant from "Fundacio Universitaria Agusti Pedro Pons". MZ was funded by the Deutsche Forschungsgemeinschaft (DFG, Germand Research Foundation; 531006414) . AD is supported by the National Institute for Health Research (NIHR) Imperial BRC, by grant funding from the European Association for the Study of the Liver (2021 Andrew Burroughs Fellowship) and from Cancer Research UK (RCCPDB-Nov21/100008) . HLR supported by Cancer Research UK (CRUK) programme grant C18342/A23390, Accelerator award C9380/A26813, the CRUK Newcastle Centre CTRQQR-2021y100003; the NIHR Newcastle Biomedical Research Centre awarded to the Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University (grant ref: 570556) and the European Commission (Horizon Europe-Mission Cancer, THRIVE, Ref. 101136622) .RM acknowledges the support from ISCIII (PI21/01619 research project and Juan Rodes contract) , SEOM (research project) , TTD (research project) and Fundacion MERCK Salud (research project) . SG was partially supported by NIH grants CA224319, DK124165, CA234212, and CA196521. DJP is supported by grant funding from the Wellcome Trust Strategic Fund (PS3416) , the Associazione Italiana per la Ricerca sul Cancro (AIRC MFAG 25697) and acknowledges grant support from the Cancer Treatment and Research Trust (CTRT) , the Foundation for Liver Research and infrastructural support by the Imperial Experimental Cancer Medicine Centre and the NIHR Imperial Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. DL was supported by an ERC Advanced Grant (101055422) and a KU Leuven Internal Fund (C14/18/092) . JML is supported by grants from European Commission (Horizon Europe-Mission Cancer, THRIVE, Ref. 101136622) , the NIH (R01-CA273932-01, R01DK56621 and R01DK128289) ; Samuel Waxman Cancer Research Foundation; the Spanish National Health Institute (MICINN, PID2022-139365OB-I00, funded by MICIU/AEI/10. 13039/501100011033 and FEDER) ; Cancer Research UK (CRUK) , Fondazione AIRC per la Ricerca sul Cancro and Fundacion Cientifica de la Asociacion Espanola Contra el Cancer (FAECC) (Accelerator Award, HUNTER, Ref. C9380/A26813) ; "la Caixa" Foundation under agreement LCF/PR/SP23/52950009; Fundacion Cientifica de la Asociacion Espanola Contra el Cancer (FAECC; Proyectos Generales, Ref. PRYGN223117LLOV; Reto AECC 70% Supervivencia: Ref. RETOS245779LLOV; and Programa de Excelencia, EPAEC246711CLIN) and the Generalitat de Catalunya/AGAUR (2021 SGR 01347) .

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

Publicated to:Journal Of Hepatology. 82 (6): - 2025-06-01 82(6), DOI: 10.1016/j.jhep.2024.12.016

Authors: Cappuyns, Sarah; Pique-Gili, Marta; Esteban-Fabro, Roger; Philips, Gino; Balaseviciute, Ugne; Pinyol, Roser; Gris-Oliver, Albert; Vandecaveye, Vincent; Abril-Fornaguera, Jordi; Montironi, Carla; Bassaganyas, Laia; Peix, Judit; Zeitlhoefler, Marcus; Mesropian, Agavni; Huguet-Pradell, Julia; Haber, Philipp K; Figueiredo, Igor; Ioannou, Giorgio; Gonzalez-Kozlova, Edgar; D'Alessio, Antonio; Mohr, Raphael; Meyer, Tim; Lachenmayer, Anja; Marquardt, Jens U; Reeves, Helen L; Edeline, Julien; Finkelmeier, Fabian; Trojan, Joerg; Galle, Peter R; Foerster, Friedrich; Minguez, Beatriz; Montal, Robert; Gnjatic, Sacha; Pinato, David J; Heikenwalder, Mathias; Verslype, Chris; Van Cutsem, Eric; Lambrechts, Diether; Villanueva, Augusto; Dekervel, Jeroen; Llovet, Josep M

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Abstract

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. (c) 2024 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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