Reversible epigenetic alterations regulate class I HLA loss in prostate cancer

Area of Science:

• Oncology
• Immunology
• Epigenetics

Background:

• Downregulation of Human Leukocyte Antigen class I (HLA-I) in prostate cancer hinders immune surveillance and checkpoint blockade therapy effectiveness.
• Molecular mechanisms driving HLA-I loss in prostate cancer remain incompletely understood.

Purpose of the Study:

• To comprehensively analyze genomic, epigenomic, and gene expression alterations of HLA-I in human prostate cancer.
• To investigate the role of epigenetic modifications in regulating HLA-I expression and its potential as a therapeutic target.

Main Methods:

• Analysis of HLA-I alterations in primary and metastatic prostate cancer tissues.
• Assessment of chromatin states, including DNA methylation and histone modifications.
• Pharmacological inhibition of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) to evaluate HLA-I re-expression.
• Co-culture experiments with T-cells to assess functional immune response.

Main Results:

• Loss of HLA-I gene expression correlated with repressive chromatin states, including DNA methylation and H3K27 trimethylation.
• DNMT and HDAC inhibition reversed epigenetic silencing, leading to increased HLA-I expression on tumor cells.
• Re-expressed HLA-I enhanced the activation of prostate-specific membrane antigen (PSMA)-specific CD8+ T-cells.
• Methylated HLA-I detected in circulating tumor cells (CTCs) suggests a potential biomarker.

Conclusions:

• HLA-I expression in prostate cancer is epigenetically regulated through reversible DNA methylation and chromatin modifications.
• Epigenetic targeted therapies hold promise for restoring HLA-I expression and improving anti-tumor immunity.
• Methylated HLA-I in CTCs may serve as a minimally invasive biomarker for patient stratification.