Cell Reports (Jul 2023)
SMYD3 represses tumor-intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck
- Nupur Nigam,
- Benjamin Bernard,
- Samantha Sevilla,
- Sohyoung Kim,
- Mohd Saleem Dar,
- Daniel Tsai,
- Yvette Robbins,
- Kyunghee Burkitt,
- Cem Sievers,
- Clint T. Allen,
- Richard L. Bennett,
- Theophilus T. Tettey,
- Benjamin Carter,
- Lorenzo Rinaldi,
- Mark W. Lingen,
- Houssein Sater,
- Elijah F. Edmondson,
- Arfa Moshiri,
- Abbas Saeed,
- Hui Cheng,
- Xiaolin Luo,
- Kevin Brennan,
- Vishal Koparde,
- Chen Chen,
- Sudipto Das,
- Thorkell Andresson,
- Abdalla Abdelmaksoud,
- Madhavi Murali,
- Seiji Sakata,
- Kengo Takeuchi,
- Raj Chari,
- Yusuke Nakamura,
- Ravindra Uppaluri,
- John B. Sunwoo,
- Carter Van Waes,
- Jonathan D. Licht,
- Gordon L. Hager,
- Vassiliki Saloura
Affiliations
- Nupur Nigam
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Benjamin Bernard
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Samantha Sevilla
- 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
- Sohyoung Kim
- Laboratory of Receptor Biology and Gene Expression, NCI, NIH, Bethesda, MD 20892, USA
- Mohd Saleem Dar
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Daniel Tsai
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Yvette Robbins
- Translational Tumor Immunology Program, NIDCD, NIH, Bethesda, MD 20892, USA
- Kyunghee Burkitt
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Cem Sievers
- Translational Tumor Immunology Program, NIDCD, NIH, Bethesda, MD 20892, USA
- Clint T. Allen
- Translational Tumor Immunology Program, NIDCD, NIH, Bethesda, MD 20892, USA
- Richard L. Bennett
- University of Florida Cancer Center, Gainesville, FL 32610, USA
- Theophilus T. Tettey
- Laboratory of Receptor Biology and Gene Expression, NCI, NIH, Bethesda, MD 20892, USA
- Benjamin Carter
- National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA
- Lorenzo Rinaldi
- Laboratory of Receptor Biology and Gene Expression, NCI, NIH, Bethesda, MD 20892, USA
- Mark W. Lingen
- University of Chicago, Department of Pathology, Chicago, IL 60637, USA
- Houssein Sater
- GU Malignancies Branch, NCI, NIH, Bethesda, MD 20892, USA
- Elijah F. Edmondson
- Molecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research, NIH, Frederick, MD 21702, USA
- Arfa Moshiri
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Abbas Saeed
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Hui Cheng
- National Institute of Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA
- Xiaolin Luo
- Ionis Pharmaceuticals, Carlsbad, CA 92010, USA
- Kevin Brennan
- Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
- Vishal Koparde
- 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
- Chen Chen
- Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
- Sudipto Das
- Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD 21702, USA
- Thorkell Andresson
- Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD 21702, USA
- Abdalla Abdelmaksoud
- 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
- Madhavi Murali
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
- Seiji Sakata
- 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
- Kengo Takeuchi
- 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
- Raj Chari
- Genome Modification Core, Laboratory Animal Sciences Program, Frederick National Lab for Cancer Research, Frederick, MD 21702, USA
- Yusuke Nakamura
- Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo 135-0063, Japan
- Ravindra Uppaluri
- Dana Farber Cancer Institute, Boston, MA 02215, USA
- John B. Sunwoo
- Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
- Carter Van Waes
- National Institute of Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA
- Jonathan D. Licht
- University of Florida Cancer Center, Gainesville, FL 32610, USA
- Gordon L. Hager
- Laboratory of Receptor Biology and Gene Expression, NCI, NIH, Bethesda, MD 20892, USA
- Vassiliki Saloura
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA; Corresponding author
- Journal volume & issue
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Vol. 42,
no. 7
p. 112823
Abstract
Summary: 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.
