Journal Article

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

Gevaert, Olivier, Tay, Joshua K., Gentles, Andrew J., Brennan, Kevin, Prunello, Marcos, Shin, June Ho, Sunwoo, John B.

2017

Overview

Chromatin modifying enzymes are frequently mutated in cancer, resulting in widespread epigenetic deregulation. Recent reports indicate that inactivating mutations in the histone methyltransferase NSD1 define an intrinsic subtype of head and neck squamous cell carcinoma (HNSC) that features pronounced DNA hypomethylation. Here, we describe a similar hypomethylated subtype of lung squamous cell carcinoma (LUSC) that is enriched for both inactivating mutations and deletions in NSD1 . The ‘NSD1 subtypes’ of HNSC and LUSC are highly correlated at the DNA methylation and gene expression levels, featuring ectopic expression of developmental transcription factors and genes that are also hypomethylated in Sotos syndrome, a congenital disorder caused by germline NSD1 mutations. Further, the NSD1 subtype of HNSC displays an ‘immune cold’ phenotype characterized by low infiltration of tumor-associated leukocytes, particularly macrophages and CD8 + T cells, as well as low expression of genes encoding the immunotherapy target PD-1 immune checkpoint receptor and its ligands. Using an in vivo model, we demonstrate that NSD1 inactivation results in reduced T cell infiltration into the tumor microenvironment, implicating NSD1 as a tumor cell-intrinsic driver of an immune cold phenotype. NSD1 inactivation therefore causes epigenetic deregulation across cancer sites, and has implications for immunotherapy.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/39 / 631/208/176/1988 / 631/250/2161 / 631/250/251 / 692/4028/67/1536 / 692/4028/67/69 / Animals / Carcinoma, Squamous Cell - immunology / Carcinoma, Squamous Cell - pathology / Carcinoma, Squamous Cell - therapy / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cell Line, Tumor / Chromatin / Deoxyribonucleic acid / Deregulation / DNA / DNA Methylation / Ectopic expression / Epigenetics / Gene expression / Head & neck cancer / Head and Neck Neoplasms - immunology / Head and Neck Neoplasms - pathology / Head and Neck Neoplasms - therapy / Histone methyltransferase / Humanities and Social Sciences / Humans / Immune checkpoint / Immunotherapy / Inactivation / Infiltration / Intracellular Signaling Peptides and Proteins - antagonists & inhibitors / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Leukocytes / Lung carcinoma / Lung Neoplasms - immunology / Lung Neoplasms - pathology / Lung Neoplasms - therapy / Lymphocytes T / Macrophages / Macrophages - immunology / Macrophages - metabolism / Metastases / Mice / Mice, Inbred NOD / multidisciplinary / Mutation / Nuclear Proteins - antagonists & inhibitors / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / PD-1 protein / Phenotype / Programmed Cell Death 1 Receptor - immunology / Programmed Cell Death 1 Receptor - metabolism / Promoter Regions, Genetic / RNA Interference / RNA, Small Interfering - metabolism / Science / Science (multidisciplinary) / Sequence Deletion / Squamous cell carcinoma / Transcription factors / Tumor Microenvironment