5-Hydroxymethylcytosine in Cell-Free DNA Predicts Immunotherapy Response in Lung Cancer

Area of Science:

• Oncology
• Epigenetics
• Biomarker Discovery

Background:

• Immune checkpoint inhibitors (ICIs) have transformed lung cancer treatment, but predicting patient response remains difficult.
• Accurate prediction of ICI response is crucial for optimizing patient outcomes and resource allocation in lung cancer therapy.

Purpose of the Study:

• To develop and validate a novel epigenetic biomarker based on 5-hydroxymethylcytosine (5hmC) in plasma cell-free DNA (cfDNA) for predicting lung cancer patient response to ICIs.
• To assess the predictive performance of the 5hmC signature compared to established biomarkers like tumor programmed death-ligand 1.

Main Methods:

• Genome-wide profiling of 5hmC in 85 plasma cfDNA samples from lung cancer patients.
• Development and validation of a 5hmC predictive model and signature using weighted predictive scores (wp-scores).
• Comparative analysis of the 5hmC signature's predictive capability against tumor programmed death-ligand 1 and assessment of associated genes and pathways.

Main Results:

• A 5hmC signature in cfDNA was significantly associated with progression-free survival (PFS) in lung cancer patients treated with ICIs.
• Low wp-scores correlated with significantly longer PFS and higher objective response rates in validation and test sets.
• The 5hmC signature demonstrated superior predictive capability and specificity for ICI treatment response compared to tumor programmed death-ligand 1.

Conclusions:

• The cfDNA 5hmC signature serves as a robust and novel biomarker for predicting ICI treatment response in lung cancer.
• This epigenetic biomarker has the potential to guide personalized treatment strategies, improving therapeutic outcomes for lung cancer patients.
• Identification of novel 5hmC-associated genes and pathways provides insights into the mechanisms underlying ICI response in lung cancer.