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

• Published in: Journal of hepatology 2024-12
• Main Authors: Cappuyns, Sarah, Piqué-Gili, Marta, Esteban-Fabró, 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, Júlia, 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, Jörg, Galle, Peter R, Foerster, Friedrich, Mínguez, Beatriz, Montal, Robert, Gnjatic, Sacha, Pinato, David J, Heikenwalder, Mathias, Verslype, Chris, Van Cutsem, Eric, Lambrechts, Diether, Villanueva, Augusto, Dekervel, Jeroen, Llovet, Josep M
• Format: Article
• Language: English
• ISSN: 1600-0641; 1600-0641
• DOI: 10.1016/j.jhep.2024.12.016

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.BACKGROUND & AIMSThe 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.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.METHODSWe 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.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.RESULTSWe 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 red