NSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma

Area of Science:

• Oncology
• Epigenetics
• Cancer Biology

Background:

• Chromatin modifying enzymes are frequently mutated in cancer, leading to epigenetic deregulation.
• Inactivating mutations in histone methyltransferase NSD1 define a subtype of head and neck squamous cell carcinoma (HNSC) with DNA hypomethylation.
• Sotos syndrome, a congenital disorder, is caused by germline NSD1 mutations.

Purpose of the Study:

• To identify and characterize a similar NSD1-mutated subtype in lung squamous cell carcinoma (LUSC).
• To investigate the correlation between NSD1 subtypes in HNSC and LUSC at methylation and gene expression levels.
• To explore the immune microenvironment and immunotherapy implications of the NSD1 subtype.

Main Methods:

• Comparative analysis of DNA methylation and gene expression data from HNSC and LUSC.
• Identification of mutations and deletions in the NSD1 gene.
• Assessment of tumor-infiltrating leukocytes (macrophages, CD8+ T cells) and immune checkpoint gene expression (PD-1).
• In vivo modeling to study the effect of NSD1 inactivation on T cell infiltration.

Main Results:

• A hypomethylated LUSC subtype enriched for NSD1 inactivating mutations and deletions was identified.
• NSD1 subtypes of HNSC and LUSC showed strong correlations in DNA methylation and gene expression, including ectopic expression of developmental genes.
• The NSD1 subtype of HNSC displayed an 'immune cold' phenotype with low immune cell infiltration and reduced expression of PD-1 pathway genes.
• In vivo models confirmed that NSD1 inactivation reduces T cell infiltration, driving an immune cold phenotype.

Conclusions:

• NSD1 inactivation defines a distinct epigenetic subtype in both HNSC and LUSC, characterized by DNA hypomethylation and altered gene expression.
• The NSD1 subtype is associated with an 'immune cold' tumor microenvironment, suggesting impaired anti-tumor immunity.
• NSD1 plays a tumor cell-intrinsic role in regulating the immune microenvironment, with significant implications for cancer immunotherapy strategies.