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SMYD3 represses tumor-intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck

  1. Author:
    Nigam, Nupur
    Bernard, Benjamin
    Sevilla, Samantha
    Kim, Sohyoung
    Dar, Mohd Saleem
    Tsai, Daniel
    Robbins, Yvette
    Burkitt, Kyunghee
    Sievers, Cem
    Allen, Clint T
    Bennett, Richard L
    Tettey, Theophilus T
    Carter, Benjamin
    Rinaldi, Lorenzo
    Lingen, Mark W
    Sater, Houssein
    Edmondson, Elijah F
    Moshiri, Arfa
    Saeed, Abbas
    Cheng, Hui
    Luo, Xiaolin
    Brennan, Kevin
    Koparde, Vishal
    Chen, Chen
    Das, Sudipto
    Andresson,Thorkell
    Abdelmaksoud,Abdalla
    Murali, Madhavi
    Sakata, Seiji
    Takeuchi, Kengo
    Chari,Raj
    Nakamura, Yusuke
    Uppaluri, Ravindra
    Sunwoo, John B
    Van Waes, Carter
    Licht, Jonathan D
    Hager, Gordon L
    Saloura, Vassiliki

  2. Author Address

    Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA., Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Laboratory of Receptor Biology and Gene Expression, NCI, NIH, Bethesda, MD 20892, USA., Translational Tumor Immunology Program, NIDCD, NIH, Bethesda, MD 20892, USA., University of Florida Cancer Center, Gainesville, FL 32610, USA., National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA., University of Chicago, Department of Pathology, Chicago, IL 60637, USA., GU Malignancies Branch, NCI, NIH, Bethesda, MD 20892, USA., Molecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research, NIH, Frederick, MD 21702, USA., National Institute of Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA., Ionis Pharmaceuticals, Carlsbad, CA 92010, USA., Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA., Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD 21702, USA., Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-0063, Japan; Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-0063, Japan., Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-0063, Japan; Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-0063, Japan; Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-0063, Japan., Genome Modification Core, Laboratory Animal Sciences Program, Frederick National Lab for Cancer Research, Frederick, MD 21702, USA., Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo 135-0063, Japan., Dana Farber Cancer Institute, Boston, MA 02215, USA., Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA. Electronic address: vassiliki.saloura@nih.gov.,
    1. Year: 2023
    2. Date: Jul 17
    3. Epub Date: 2023 07 17
  2. Journal: Cell Reports
    1. 42
    2. 7
    3. Pages: 112823
  4. Type of Article: Article
  5. Article Number: 112823
  1. Abstract:

    Cancers often display immune escape, but the mechanisms are incompletely understood. Herein, we identify SMYD3 as a mediator of immune escape in human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), an aggressive disease with poor response to immunotherapy with pembrolizumab. SMYD3 depletion induces upregulation of multiple type I interferon (IFN) response and antigen presentation machinery genes in HNSCC cells. Mechanistically, SMYD3 binds to and regulates the transcription of UHRF1, encoding for a reader of H3K9me3, which binds to H3K9me3-enriched promoters of key immune-related genes, recruits DNMT1, and silences their expression. SMYD3 further maintains the repression of immune-related genes through intragenic deposition of H4K20me3. In vivo, Smyd3 depletion induces influx of CD8+ T cells and increases sensitivity to anti-programmed death 1 (PD-1) therapy. SMYD3 overexpression is associated with decreased CD8 T cell infiltration and poor response to neoadjuvant pembrolizumab. These data support combining SMYD3 depletion strategies with checkpoint blockade to overcome anti-PD-1 resistance in HPV-negative HNSCC. Published by Elsevier Inc.

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External Sources

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  2. DOI: 10.1016/j.celrep.2023.112823
  3. PMID: 37463106
  4. PII : S2211-1247(23)00834-3

Library Notes

  1. Fiscal Year: FY2022-2023
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