Single-cell RNA seq-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma - Centre Eugène Marquis
Article Dans Une Revue Journal of Hepatology Année : 2025

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

1 University Hospitals Leuven [Leuven]
2 VIB-KU-CCB - Leuven Center for Cancer Biology
3 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
4 MSSM - Icahn School of Medicine at Mount Sinai [New York]
5 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
6 Clinic Barcelona Hospital Universitari
7 IGF - Institut de Génomique Fonctionnelle
8 Charité - UniversitätsMedizin = Berlin University Medicine
9 Hammersmith Hospital NHS Imperial College Healthcare
10 Imperial College London
11 Royal Free Hospital [London, UK]
12 UCL - University College of London [London]
13 Inselspital - Bern University Hospital [Berne]
14 UKSH - University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein
15 Biosciences Institute, Faculty of Medical Sciences [Newcastle]
16 NICR - Northern Institute for Cancer Research [Newcastle]
17 Freeman Hospital
18 Newcastle Upon Tyne Hospitals NHS Foundation Trust
19 CRLCC - CRLCC Eugène Marquis
20 Frankfurt University Hospital
21 University Medical Center of the Johannes Gutenberg-University Mainz
22 Vall d'Hebron University Hospital [Barcelona]
23 VHIR - Vall d’Hebron Research Institute
24 CIBERehd - Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas
25 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
26 Universitat de Lleida
27 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
28 ICREA - Institució Catalana de Recerca i Estudis Avançats = Catalan Institution for Research and Advanced Studies
Laia Bassaganyas
Anja Lachenmayer
Julien Edeline
Robert Montal

Résumé

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 versus 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 advanced HCC patients treated with atezo+bev (n=317) versus 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 characterized 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 versus 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.
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hal-04867696 , version 1 (06-01-2025)

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Sarah Cappuyns, Marta Piqué-Gili, Roger Esteban-Fabró, Gino Philips, Ugne Balaseviciute, et al.. Single-cell RNA seq-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma. Journal of Hepatology, In press, ⟨10.1016/j.jhep.2024.12.016⟩. ⟨hal-04867696⟩
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