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

作者：Sarah Cappuyns, Marta Piqué‐Gili, Roger Esteban-Fabró, Gino Philips, Ugne Balaseviciute, Roser Pinyol, Albert Gris‐Oliver, Vincent Vandecaveye, Jordi Abril‐Fornaguera, Carla Montironi, Laia Bassaganyas, Judit Peix, Marcus Zeitlhoefler, Agavni Mesropian, Júlia Huguet‐Pradell, Philipp K. Haber, Igor Figueiredo, Giorgio Ioannou, Edgar Gonzalez‐Kozlova, Antonio D’Alessio, Raphael Mohr, Tim Meyer, Anja Lachenmayer, Jens U. Marquardt, Helen L. Reeves, Julien Edeline, Fabian Finkelmeier, Jörg Trojan, Peter R. Galle, Friedrich Foerster, Beatriz Mínguez, Robert Montal, Sacha Gnjatic, David J. Pinato, Mathias Heikenwälder, Chris Verslype, Eric Van Cutsem, Diether Lambrechts, Augusto Villanueva, Jeroen Dekervel, Josep M. Llovet · 发表于：Journal of Hepatology · 年份：2024 · DOI：10.1016/j.jhep.2024.12.016 · 被引用次数：61 · 研究领域：Single-cell and spatial transcriptomics、Cancer Immunotherapy and Biomarkers、Ferroptosis and cancer prognosis

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. so...