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| Home > Publications database > Circulating extracellular vesicles carrying PD-1, PD-L1 and CTLA-4 inform resistance to anti-PD-L1-based therapy in HCC. |
| Home > Publications database > Circulating extracellular vesicles carrying PD-1, PD-L1 and CTLA-4 inform resistance to anti-PD-L1-based therapy in HCC. |
| Journal Article | DKFZ-2026-01952 |
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2026
BMJ Publishing Group
London
Abstract: First-line immune checkpoint inhibitor (ICI) therapy has contributed to improved outcomes in hepatocellular carcinoma (HCC). However, only around 30% of patients respond, highlighting the need for biomarker-driven patient selection. Considering the lack of tissue acquirement in HCC in clinical routine, liquid biopsy holds great promise.We aimed at profiling immune checkpoints (IC) on circulating extracellular vesicles (EVs) as potential liquid biopsy-based biomarkers for prediction of treatment response.Three distinct cohorts were analysed in this study: (1) HCC explorer cohort (n=40), testing the presence of membrane-bound ICs on EVs; (2) early-stage HCC cohort (n=37 with paired blood and tissue), assessing the interplay between EV and tissue ICs alongside clinicopathological parameters and (3) treatment cohort (n=202 with 600 sequential blood samples), comprising an ICI treated cohort with a training (n=79, n=402 sequential samples) and a validation group (n=82, n=146 sequential samples), alongside a tyrosine-kinase inhibitor (TKI) treated cohort (n=41, n=52 sequential samples), to identify predictors of immunotherapy response through IC profiling of circulating EVs via multiplex immunoassay.Programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) were enriched in EV fractions compared to EV-depleted serum. Baseline and early dynamics of EV-IC levels significantly discriminated between responders and non-responders in the ICI-treated training and validation cohorts, while simultaneously predicting progression-free survival (PFS) and overall survival (OS). These findings were not reproducible in the TKI-treated cohort. In addition, dynamic changes of EV-IC levels during therapy in patients with initial response predicted acquired therapeutic resistance, approximately 36-42 weeks before progression was traceable on imaging.EVs carrying PD-1, PD-L1 and CTLA-4 represent readily quantifiable, non-invasive biomarkers to predict response and survival in patients with advanced HCC undergoing ICI therapy and serve to identify biological ICI resistance much earlier than current standards with imaging.
Keyword(s): BIOMARKERS ; HEPATOCELLULAR CARCINOMA ; IMMUNE RESPONSE ; IMMUNOTHERAPY
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