Histone methylation antagonism drives tumor immune evasion in squamous cell carcinomas

Area of Science:

• Cancer Biology
• Epigenetics
• Immunology

Background:

• Chromatin abnormalities in cancer impact tumor-immune interactions.
• DNA hypomethylation and retrotransposon activation are linked to anti-tumor immunity via interferon response.
• The role of histone H3K36 methyltransferase NSD1 in this context is unclear.

Purpose of the Study:

• Investigate how NSD1 inactivation affects tumor-immune interactions in squamous cell carcinomas (SCCs).
• Elucidate the molecular mechanisms by which NSD1 loss influences immune evasion.
• Identify potential therapeutic targets to restore anti-tumor immunity in NSD1-mutant tumors.

Main Methods:

• Utilized syngeneic and genetically engineered mouse models of head and neck SCCs.
• Analyzed chromatin modifications (H3K36me2, H3K27me3) and gene expression.
• Assessed immune cell infiltration and interferon response.
• Investigated the effect of EZH2 inhibition.

Main Results:

• NSD1-deficient SCCs showed immune exclusion and reduced interferon response despite DNA hypomethylation and high retrotransposon expression.
• NSD1 loss led to silencing of innate immunity genes, including IFNLR1, via H3K36me2 depletion and H3K27me3 gain.
• EZH2 inhibition restored immune infiltration and impaired tumor growth in Nsd1-mutant models.

Conclusions:

• NSD1 inactivation promotes immune evasion in SCCs through epigenetic silencing of innate immunity genes.
• Chromatin cross-talk involving H3K36me2 and H3K27me3 regulates the viral mimicry response.
• Targeting EZH2 represents a promising strategy to overcome immune evasion in DNA hypomethylated tumors.