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
Digestive Oncology, Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium; Laboratory of Clinical Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium; Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium; VIB Centre for Cancer Biology, Leuven, Belgium; Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.
Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain.
J Hepatol. 2025 Jun;82(6):1036-1049. doi: 10.1016/j.jhep.2024.12.016. Epub 2024 Dec 19.
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.
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.
阿替利珠单抗和贝伐单抗联合使用（阿替利珠单抗+贝伐单抗）是晚期肝细胞癌（HCC）目前的标准治疗方案，其总生存期（OS）中位数为19.2个月。在此，我们旨在揭示驱动临床获益与对阿替利珠单抗+贝伐单抗耐药的潜在细胞过程。
我们利用晚期HCC的单细胞RNA测序技术，得出概括21种细胞表型的基因表达特征。将这些特征应用于422例接受阿替利珠单抗+贝伐单抗治疗的晚期HCC患者的RNA测序样本（n = 317），并与接受阿替利珠单抗（n = 47）或索拉非尼（n = 58）治疗的患者样本作为对照。
我们揭示了对阿替利珠单抗+贝伐单抗两种不同的反应模式。首先，一种免疫介导的反应，其特征是CD8 + T效应细胞和促炎性CXCL10 +巨噬细胞同时存在，代表免疫丰富的微环境。其次，一种非免疫、与血管生成相关的反应，其特征是血管内皮生长因子（VEGF）共受体神经纤毛蛋白-1（NRP1）表达降低，该生物标志物可特异性预测阿替利珠单抗+贝伐单抗对比索拉非尼治疗时OS改善情况（p = 0.039）。原发性耐药与免疫抑制性髓系细胞群（即CD14 +单核细胞和TREM2 +巨噬细胞）富集以及Notch通路激活有关。基于这些机制性见解，我们定义了“免疫活性”和“血管生成驱动”分子亚组，每个亚组接受阿替利珠单抗+贝伐单抗治疗时OS均显著长于索拉非尼（交互作用p = 0.027），以及一个“耐药”亚组。
我们的研究揭示了晚期HCC中对阿替利珠单抗加贝伐单抗临床获益的两种不同分子亚组（“免疫活性”和“血管生成驱动”）以及该治疗原发性耐药的主要特征，从而提供了一个基于临床结果对患者进行分层的分子框架，并指导克服耐药性的潜在策略。
阿替利珠单抗+贝伐单抗是晚期肝细胞癌（HCC）的标准治疗方案，但该联合治疗临床获益的分子决定因素仍不清楚。本研究利用单细胞RNA测序技术，得出代表晚期HCC微环境中21种细胞亚型的基因表达特征。通过将这些特征应用于RNA测序样本，我们揭示了对阿替利珠单抗+贝伐单抗两种不同的反应模式，并定义了在接受阿替利珠单抗+贝伐单抗治疗时具有不同临床结果的患者分子亚组（“免疫活性”和“血管生成驱动”对比“耐药”），指出免疫抑制性髓系细胞类型和Notch通路激活在对阿替利珠单抗+贝伐单抗原发性耐药中的作用。这些结果可能有助于优化治疗策略并改善晚期HCC患者预后，同时也指导旨在克服耐药机制的未来研究。
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