2. Academic Validation
  3. Histone methylation antagonism drives tumor immune evasion in squamous cell carcinomas

Histone methylation antagonism drives tumor immune evasion in squamous cell carcinomas

  • Mol Cell. 2022 Sep 29;S1097-2765(22)00896-6. doi: 10.1016/j.molcel.2022.09.007.
Yinglu Li 1,  Elizabeth M Goldberg 1,  Xiao Chen 1,  Xinjing Xu 1,  John T McGuire 1,  Giuseppe Leuzzi 1,  Dimitris Karagiannis 1,  Tiffany Tate 2,  Nargess Farhangdoost 3,  Cynthia Horth 3,  Esther Dai 1,  Zhiming Li 4,  Zhiguo Zhang 5,  Benjamin Izar 6,  Jianwen Que 7,  Alberto Ciccia 8,  Jacek Majewski 3,  Angela J Yoon 9,  Laurie Ailles 10,  Cathy Lee Mendelsohn 11,  Chao Lu 12
Affiliations

Affiliations

  • 1 Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 2 Department of Urology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 3 Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University Genome Centre, Montreal, QC H3A 0G1, Canada.
  • 4 Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 5 Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA; Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 6 Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Medicine, Division of Hematology and Oncology, Columbia University Irving Medical Center, New York, NY 10032, USA; Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 7 Division of Digestive and Liver Diseases, Department of Medicine, Columbia Center for Human Development, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 8 Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 9 Division of Oral and Maxillofacial Pathology, Columbia University College of Dental Medicine and Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 10 Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • 11 Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Urology, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 12 Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: [email protected].
PMID: 36206767 DOI: 10.1016/j.molcel.2022.09.007
Abstract

How cancer-associated chromatin abnormalities shape tumor-immune interaction remains incompletely understood. Recent studies have linked DNA hypomethylation and de-repression of retrotransposons to anti-tumor immunity through the induction of interferon response. Here, we report that inactivation of the histone H3K36 methyltransferase NSD1, which is frequently found in squamous cell carcinomas (SCCs) and induces DNA hypomethylation, unexpectedly results in diminished tumor immune infiltration. In syngeneic and genetically engineered mouse models of head and neck SCCs, NSD1-deficient tumors exhibit immune exclusion and reduced interferon response despite high retrotransposon expression. Mechanistically, NSD1 loss results in silencing of innate immunity genes, including the type III interferon receptor IFNLR1, through depletion of H3K36 di-methylation (H3K36me2) and gain of H3K27 tri-methylation (H3K27me3). Inhibition of EZH2 restores immune infiltration and impairs the growth of Nsd1-mutant tumors. Thus, our work uncovers a druggable chromatin cross talk that regulates the viral mimicry response and enables immune evasion of DNA hypomethylated tumors.

Keywords

DNA methylation; EZH2; NSD1; Tazemetostat; epigenetics; head and neck cancers; histone methylation; immune evasion; squamous cell carcinomas.

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