BibTex format
@article{Lombardi:2026:10.1016/j.jhep.2026.05.018,
author = {Lombardi, P and Ramon-Gil, E and Raja, RQ and Brunetti, L and Manfredi, GF and Zhou, Z and Merces, G and Cappuyns, S and Maria, Fulgenzi CA and D'Alessio, A and Torkpour, A and Celsa, C and Stefanini, B and Yang, H and Crowley, F and Marron, TU and Saeed, A and Pinter, M and Scheiner, B and Huang, Y-H and Lee, P-C and Nishida, N and Po-Ting, Lin R and Dalbeni, A and Vivaldi, C and Masi, G and Rohlen, N and von, Felden J and Kaseb, A and Galle, PR and Kudo, M and Hsu, W-F and Rimassa, L and Parisi, A and Kelley, RK and Toyoda, H and Pirisi, M and Jabar, F and Rakaee, M and Cabibbo, G and Cammà, C and Piscaglia, F and Hwang, S and Shin, DJ and Li, M and Dekervel, J and Guerra, N and Meyer, T and Reeves, HL and Bengsch, B and Daniele, G and Mann, DA and Chon, HJ and Leslie, J and Pinato, DJ},
doi = {10.1016/j.jhep.2026.05.018},
journal = {J Hepatol},
pages = {899--911},
title = {A myeloid immunosuppressive phenotype defines primary refractoriness to atezolizumab plus bevacizumab in hepatocellular carcinoma.},
url = {http://dx.doi.org/10.1016/j.jhep.2026.05.018},
volume = {85},
year = {2026}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - 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 TME enriched in CD163+ tumour-associated macrophages and vascular cancer-associated fibroblasts, a higher Treg/Teff cell ratio, and pro-tumour supportive cellular interactions. RNA-seq 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
AU - Lombardi,P
AU - Ramon-Gil,E
AU - Raja,RQ
AU - Brunetti,L
AU - Manfredi,GF
AU - Zhou,Z
AU - Merces,G
AU - Cappuyns,S
AU - Maria,Fulgenzi CA
AU - D'Alessio,A
AU - Torkpour,A
AU - Celsa,C
AU - Stefanini,B
AU - Yang,H
AU - Crowley,F
AU - Marron,TU
AU - Saeed,A
AU - Pinter,M
AU - Scheiner,B
AU - Huang,Y-H
AU - Lee,P-C
AU - Nishida,N
AU - Po-Ting,Lin R
AU - Dalbeni,A
AU - Vivaldi,C
AU - Masi,G
AU - Rohlen,N
AU - von,Felden J
AU - Kaseb,A
AU - Galle,PR
AU - Kudo,M
AU - Hsu,W-F
AU - Rimassa,L
AU - Parisi,A
AU - Kelley,RK
AU - Toyoda,H
AU - Pirisi,M
AU - Jabar,F
AU - Rakaee,M
AU - Cabibbo,G
AU - Cammà,C
AU - Piscaglia,F
AU - Hwang,S
AU - Shin,DJ
AU - Li,M
AU - Dekervel,J
AU - Guerra,N
AU - Meyer,T
AU - Reeves,HL
AU - Bengsch,B
AU - Daniele,G
AU - Mann,DA
AU - Chon,HJ
AU - Leslie,J
AU - Pinato,DJ
DO - 10.1016/j.jhep.2026.05.018
EP - 911
PY - 2026///
SP - 899
TI - A myeloid immunosuppressive phenotype defines primary refractoriness to atezolizumab plus bevacizumab in hepatocellular carcinoma.
T2 - J Hepatol
UR - http://dx.doi.org/10.1016/j.jhep.2026.05.018
UR - https://www.ncbi.nlm.nih.gov/pubmed/42297215
VL - 85
ER -