DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load

Area of Science:

• Cancer Epigenetics
• Immunotherapy Biomarkers
• Genomic Instability

Background:

• Mitotic cell division influences tumor mutation burden and copy number load, which are predictive markers for immunotherapy response.
• Cell division is linked to genomic demethylation, particularly in late-replicating domains, affecting gene expression.
• Immunomodulatory genes are found in these demethylated regions and can be transcriptionally repressed in tumors with specific methylation patterns.

Purpose of the Study:

• To investigate the relationship between DNA methylation alterations, tumor mutation burden, and immune evasion in cancer.
• To determine if global methylation loss or mutation burden has higher predictive power for immunotherapy response.
• To explore the role of epigenetic modulation via DNA methylation in immunotherapy resistance.

Main Methods:

• Analysis of methylome data from lung cancer (n=141) and melanoma (n=40) cohorts.
• Correlation analysis between global methylation loss, mutation burden, aneuploidy, and immune evasion signatures.
• Assessment of gene expression patterns in relation to DNA methylation status, particularly in immunomodulatory genes.

Main Results:

• Global methylation loss correlated with immune evasion signatures, independent of mutation burden and aneuploidy.
• Genomic methylation alterations were found to counteract the effect of high mutation burden, increasing resistance to immunotherapy.
• Methylation loss showed higher predictive power for immunotherapy response than mutation burden.
• Genomic hypomethylation was associated with immune escape signatures in aneuploid tumors.

Conclusions:

• DNA methylation alterations play a significant role in epigenetic modulation and influence immunotherapy outcomes.
• Global DNA hypomethylation is a key mechanism driving immune evasion and immunotherapy resistance, even in tumors with high mutation burden.
• Epigenetic modifications, specifically DNA methylation patterns, are crucial determinants of therapeutic response and warrant consideration in precision immunotherapy strategies.