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Publications

Journal Article Ahead of print 3 citations

PubMed: 42297215 DOI: 10.1016/j.jhep.2026.05.018

A myeloid immunosuppressive phenotype defines primary refractoriness to atezolizumab Plus bevacizumab in hepatocellular caarcinoma.

J Hepatol

Authors: 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, Hannah Yang, Fionnuala Crowley, Thomas U Marron, Anwaar Saeed, Matthias Pinter, Bernhard Scheiner, Yi-Hsiang Huang, Pei-Chang Lee, Naoshi Nishida, Ryan 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 … and 5 other authors

Affiliations

  • Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK; Phase 1 Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.
  • The Newcastle University Centre for Cancer, Newcastle University, Newcastle Upon Tyne, U.K.
  • Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK.
  • Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK; Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
  • Image Analysis Unit, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK; Digestive Oncology, Department of Gastroenterology and Hepatology, UZ/KU Leuven, Belgium.
  • Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK; Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy.
  • Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK; Department of Medical and Surgical Sciences, University of Bologna, Italy.
  • Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.
  • Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA.
  • Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
  • Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
  • Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
  • Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.
  • Department of Gastroenterology and Hepatology, Chang Gung Medical Foundation, Linkou Chang Gung Memorial Hospital, Taiwan NO 5, Fu-Hsing Street, Kuei Shan, Taoyuan 333, Taiwan.
  • University of Verona, Department of Medicine General Medicine C Unit & Liver Unit.
  • Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
  • Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, University of Freiburg, Freiburg, Germany.
  • Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Gastrointestinal Medical Oncology Department, University of Texas MD Anderson Cancer Center, Houston, TX.
  • University Medical Center Mainz, I. Dept. of Internal Medicine, Mainz, Germany.
  • Department of Internal Medicine, Center for Digestive Medicine, China Medical University Hospital, Taichung, Taiwan.
  • Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy; Hepatopancreatobiliary Oncology , Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via A. Manzoni 56, 20089 Rozzano, Milan, Italy.
  • Department of Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria delle Marche, Ancona, Italy.
  • Department of Medicine (Hematology/Oncology), UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.
  • Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan.
  • Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
  • Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK; Department of Clinical Pathology, University Hospital of North Norway, Tromsø, Norway.
  • Department of Clinical Pathology, University Hospital of North Norway, Tromsø, Norway; Department of Cancer Genetics, Oslo University Hospital, Oslo, Norway; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway.
  • Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy; Department of Surgical, Oncological and Oral Sciences (Di.Chir.On.S.), University of Palermo, Italy.
  • Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy.
  • Department of Medical and Surgical Sciences, University of Bologna, Italy; Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy.
  • Department of Pathology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea.
  • Department of Biomedical Science, College of Life Science, CHA University School of Medicine, Seongnam, Republic of Korea.
  • Division of Gastroenterology and Hepatology, University of California, San Francisco, California, USA.
  • Digestive Oncology, Department of Gastroenterology and Hepatology, UZ/KU Leuven, Belgium.
  • Department of Life Sciences, Imperial College London, South Kensington Campus, Exhibition Road, London, SW7 2AZ, UK.
  • Research Department of Oncology, UCL Cancer Institute, University College London, Royal Free Hospital, London, UK.
  • The Newcastle University Centre for Cancer, Newcastle University, Newcastle Upon Tyne, U.K; Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK; NIHR, Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK.

Abstract

BACKGROUND

Despite improved outcomes with atezolizumab plus bevacizumab (A+B) in hepatocellular carcinoma (HCC), primary refractoriness (PRef), characterised by early progression or short-lived disease stabilisation following treatment, remains a significant challenge.

METHODS

We analysed 1296 patients with HCC treated with frontline A+B (AB-real) and validated findings in 645 trial participants recruited to IMbrave150 and GO30140. PRef was defined by Society for the Immunotherapy of Cancer (SITC) criteria. We performed a multi-parametric analysis of pre-treatment tumour tissue, including machine learning-based quantification of tumour-infiltrating lymphocytes, imaging mass cytometry (IMC) and RNA sequencing (RNAseq) to evaluate differences in the tumour microenvironment (TME) of PRef versus responding patients. Two independent cohorts were further used to refine the TME characterisation through single-cell RNA sequencing (n=20) and IMC (n=16). We employed conditional inference tree analyses to provide a hierarchical organisation of PRef determinants.

RESULTS

Among 677 AB-real and 378 trial patients evaluable by SITC criteria, PRef identified inferior median OS in comparison with responding patients (AB-real: 7.3 vs. 31.5 months,p<0.001; Trials: 10.8 vs. NR, p<0.001). PRef patients exhibited higher baseline systemic inflammation (NLR≥3), a distinctively immunosuppressive TME enriched in CD163 + tumour-associated macrophages, vascular cancer-associated fibroblasts, a higher T reg/T eff ratio, and pro-tumour supportive cellular interactions. RNAseq of tumour tissue confirmed lower intrinsic immunogenicity in PRef samples with elevated myeloid infiltration. Conditional inference tree analysis identified IFN-γ signature downregulation combined with NLR≥3 as the strongest contributor of PRef.

CONCLUSIONS

PRef to A+B identifies a distinct biological entity characterised by unopposed systemic inflammation, myeloid infiltration and T-cell depletion. Targeting myeloid-mediated immunosuppression, particularly in patients with low IFN-γ signature expression and elevated NLR might enhance responsiveness to A+B.

IMPACT AND IMPLICATIONS

Atezolizumab plus bevacizumab represents the standard first-line treatment for unresectable HCC, yet the biological basis of early treatment failure remains poorly understood. In this multi-cohort translational study, we show that approximately 40% of patients exhibit primary refractoriness according to SITC criteria - clinically validated here for the first time in HCC - and identify a distinct immunomolecular profile of primary refractory tumours characterised by IFN-γ pathway repression, unfavourable myeloid polarisation, and a distinct spatial immune architecture. These findings provide a biological framework that may inform the design of biomarker-stratified trials and rational combination strategies to overcome primary resistance to first-line immunotherapy.

MeSH

Liver Diseases, Cells, Phenotype, Multiple Chronic Conditions, Bevacizumab, Liver, Immunotherapy, Therapeutics, Tissues