A myeloid immunosuppressive phenotype defines primary refractoriness to atezolizumab plus bevacizumab in hepatocellular carcinoma

作者：Pasquale Lombardi, Erik Ramon‐Gil, Rabial Q. Raja, Leonardo Brunetti, Giulia Francesca Manfredi, Zhongguo Zhou, George Merces, Sarah Cappuyns, Claudia Angela Maria Fulgenzi, Antonio D’Alessio, Aria Torkpour, Ciro Celsa, Bernardo Stefanini, H. J. Yang, Fionnuala Crowley, Thomas U. Marron, Anwaar Saeed, Matthias Pinter, B Scheiner, Yi‐Hsiang Huang, Pei‐Chang Lee, Naoshi Nishida, Po‐Ting Lin, Andrea Dalbeni, Caterina Vivaldi, Gianluca Masi, Natascha Rohlen, Johann von Felden, Ahmed Kaseb, Peter R. Galle, Masatoshi Kudo, Wei‐Fan Hsu, Lorenza Rimassa, Alessandro Parisi, Robin Kate Kelley, Hidenori Toyoda, Mario Pirisi, Falah Jabar, Mehrdad Rakaee, Giuseppe Cabibbo, Calogero Cammà, Fabio Piscaglia, Sohyun Hwang, Dong Jun Shin, Michael Li, Jeroen Dekervel, Nadia Guerra, Tim Meyer, Helen L. Reeves, Bertram Bengsch, Gennaro Daniele, Derek A. Mann, Hong Jae Chon, Jack Leslie, David J. Pinato · 发表于：Journal of Hepatology · 年份：2026 · DOI：10.1016/j.jhep.2026.05.018 · 被引用次数：2 · 研究领域：Hepatocellular Carcinoma Treatment and Prognosis、Cancer Immunotherapy and Biomarkers、Immune cells in cancer

BACKGROUND & AIMS: Despite improved outcomes with atezolizumab plus bevacizumab (A+B) in hepatocellular carcinoma, primary refractoriness (PRef), characterised by early progression or short-lived disease stabilisation following treatment, remains a significant challenge. METHODS: We analysed 1,296 patients with hepatocellular carcinoma treated with frontline A+B (AB-real) and validated findings in 645 trial participants recruited to IMbrave150 and GO30140. PRef was defined by SITC (Society for the Immunotherapy of Cancer) criteria. We performed a multi-parametric analysis of pre-treatment tumour tissue, including machine learning-based quantification of tumour-infiltrating lymphocytes, imaging mass cytometry and RNA sequencing (RNA-seq) to evaluate differences in the tumour microenvironment (TME) of patients with PRef vs. responders. Two independent cohorts were further used to refine the TME characterisation through single-cell RNA-seq (n = 20) and imaging mass cytometry (n = 16). We employed conditional inference tree analyses to provide a hierarchical organisation of PRef determinants. RESULTS: Among 677 AB-real patients and 378 trial participants evaluable by SITC criteria, PRef was associated with inferior median overall survival compared to response (AB-real: 7.3 vs. 31.5 months, p <0.001; Trials: 10.8 vs. not reached, p <0.001). Patients with PRef exhibited higher baseline systemic inflammation (neutrophil-to-lymphocyte ratio [NLR] ≥3), a distinctly immunosuppressive T...