Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma
Philipp K Haber1, Florian Castet2, Miguel Torres-Martin2
1Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York, New York, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, Department of Surgery, Recanti/Miller Transplant Institute at the Icahn School of Medicine at Mount Sinai, New York, New York, Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Surgery, Campus Charité Mitte and Campus Virchow Klinikum, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.
Background & 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, we 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. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response.
Results:
Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II-related antigen presentation. We 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 HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.
Insights
A new 11-gene signature (IFNAP) identifies responders to anti-PD1 immunotherapy in advanced hepatocellular carcinoma (aHCC). This signature, based on interferon signaling and MHC II, predicts response in frontline treatment but not after tyrosine kinase inhibitors (TKIs).
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Advanced hepatocellular carcinoma (aHCC) shows limited response to anti-PD1 inhibitors.
- Molecular mechanisms driving anti-PD1 response in aHCC remain largely unknown.
- Understanding these mechanisms is crucial for improving patient outcomes.
Purpose of the Study:
- To identify molecular and immune traits associated with anti-PD1 response in aHCC.
- To develop a predictive biomarker for immunotherapy response in aHCC.
- To investigate the impact of prior treatments on immunotherapy response.
Main Methods:
- Analysis of molecular and immune profiles from 111 aHCC tumor samples.
- Utilized whole-genome expression data, mutational analysis, and histologic evaluation.
- Developed and validated an 11-gene signature (IFNAP) for response prediction.
Main Results:
- Responders to frontline anti-PD1 therapy exhibited upregulated interferon-γ signaling and MHC II antigen presentation.
- The 11-gene IFNAP signature accurately predicted response and survival in frontline aHCC patients.
- The IFNAP signature's predictive power was lost in patients pretreated with tyrosine kinase inhibitors (TKIs).
Conclusions:
- Interferon signaling and MHC-II related genes are critical for anti-PD1 response in aHCC.
- The IFNAP signature serves as a promising predictive biomarker for frontline immunotherapy in aHCC.
- Biopsies prior to immunotherapy are essential to identify predictive biomarkers and guide treatment decisions, especially after TKI therapy.
