TY - JOUR
T1 - Single-cell RNA seq-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma
AU - Cappuyns, Sarah
AU - Piqué-Gili, Marta
AU - Esteban-Fabró, Roger
AU - Philips, Gino
AU - Balaseviciute, Ugne
AU - Pinyol, Roser
AU - Gris-Oliver, Albert
AU - Vandecaveye, Vincent
AU - Abril-Fornaguera, Jordi
AU - Montironi, Carla
AU - Bassaganyas, Laia
AU - Peix, Judit
AU - Zeitlhoefler, Marcus
AU - Mesropian, Agavni
AU - Huguet-Pradell, Júlia
AU - Haber, Philipp K
AU - Figueiredo, Igor
AU - Ioannou, Giorgio
AU - Gonzalez-Kozlova, Edgar
AU - D'Alessio, Antonio
AU - Mohr, Raphael
AU - Meyer, Tim
AU - Lachenmayer, Anja
AU - Marquardt, Jens U
AU - Reeves, Helen L
AU - Edeline, Julien
AU - Finkelmeier, Fabian
AU - Trojan, Jörg
AU - Galle, Peter R
AU - Foerster, Friedrich
AU - Mínguez, Beatriz
AU - Montal, Robert
AU - Gnjatic, Sacha
AU - PINATO, David James
AU - Heikenwalder, Mathias
AU - Verslype, Chris
AU - Van Cutsem, Eric
AU - Lambrechts, Diether
AU - Villanueva, Augusto
AU - Dekervel, Jeroen
AU - Llovet, Josep M
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - Advanced Hepatocellular Carcinoma
KW - Atezolizumab and bevacizumab
KW - Biomarkers of Response
KW - Primary Resistance
KW - Single-Cell RNA-Sequencing
KW - Advanced Hepatocellular Carcinoma
KW - Atezolizumab and bevacizumab
KW - Biomarkers of Response
KW - Primary Resistance
KW - Single-Cell RNA-Sequencing
UR - https://iris.uniupo.it/handle/11579/202268
U2 - 10.1016/j.jhep.2024.12.016
DO - 10.1016/j.jhep.2024.12.016
M3 - Article
SN - 0168-8278
JO - Journal of Hepatology
JF - Journal of Hepatology
ER -