Liver and Bile
Gastroenterology. 2023;164(1):72–88.e18
Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma
Background and aims: Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (~20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, the authors herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1.
Methods: Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. Molecular analysis and immune deconvolution were performed using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an end point of objective response.
Results: Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKIs) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II-related antigen presentation. The authors generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and > 240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy.
Conclusion: Interferon signaling and major histocompatibility complex-related genes are key molecular features of hepatocellular carcinomas (HCCs) responding to anti-PD1. A novel 11-gene signature predicts response in frontline advanced HCC, but not in patients pretreated with tyrosine kinase inhibitors. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.