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| Pàgina inicial > Articles > Articles publicats > Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma |
(Universitat de Barcelona) (Universitat de Barcelona) (Universitat de Barcelona) (Universitat de Barcelona) (Institut de Génomique Fonctionnelle) (University Hospital Bern) (Newcastle University Translational and Clinical Research Institute and Newcastle University Centre for Cancer) (Universitat Autònoma de Barcelona. Departament de Medicina) (Università Del Piemonte Orientale "A. Avogadro") (UZ Leuven (Bèlgica)) (Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai) (Hospital Clínic i Provincial de Barcelona)
| Data: | 2025 |
| Resum: | 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. |
| Ajuts: | Agencia Estatal de Investigación BES-2017-081286 Agencia Estatal de Investigación PID2022-139365OB-I00 Generalitat de Catalunya 2021/SGR-00338 European Commission 101136622 "la Caixa" Foundation LCF/PR/SP23/5295000 Generalitat de Catalunya 2021/SGR-01347 |
| Drets: | Aquest 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.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | Advanced Hepatocellular Carcinoma ; Atezolizumab and bevacizumab ; Biomarkers of Response ; Single-Cell RNA-Sequencing ; Primary Resistance |
| Publicat a: | Journal of hepatology, Vol. 82, Num. 6 (June 2025) , p. 1036-1049, ISSN 1600-0641 |
