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

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 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 hepatocellular carcinoma, 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 hepatocellular carcinoma - and identify a distinct immuno-molecular 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.