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

doi:10.1016/j.celrep.2023.112823

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

Cell Rep. 2023 Jul 25;42(7):112823. doi: 10.1016/j.celrep.2023.112823. Epub 2023 Jul 17.

Authors

Nupur Nigam¹, Benjamin Bernard¹, Samantha Sevilla², Sohyoung Kim³, Mohd Saleem Dar¹, Daniel Tsai¹, Yvette Robbins⁴, Kyunghee Burkitt¹, Cem Sievers⁴, Clint T Allen⁴, Richard L Bennett⁵, Theophilus T Tettey³, Benjamin Carter⁶, Lorenzo Rinaldi³, Mark W Lingen⁷, Houssein Sater⁸, Elijah F Edmondson⁹, Arfa Moshiri¹, Abbas Saeed¹, Hui Cheng¹⁰, Xiaolin Luo¹¹, Kevin Brennan¹², Vishal Koparde², Chen Chen¹², Sudipto Das¹³, Thorkell Andresson¹³, Abdalla Abdelmaksoud², Madhavi Murali¹, Seiji Sakata¹⁴, Kengo Takeuchi¹⁵, Raj Chari¹⁶, Yusuke Nakamura¹⁷, Ravindra Uppaluri¹⁸, John B Sunwoo¹², Carter Van Waes¹⁰, Jonathan D Licht⁵, Gordon L Hager³, Vassiliki Saloura¹⁹

Affiliations

¹ Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
² 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.
³ Laboratory of Receptor Biology and Gene Expression, NCI, NIH, Bethesda, MD 20892, USA.
⁴ Translational Tumor Immunology Program, NIDCD, NIH, Bethesda, MD 20892, USA.
⁵ University of Florida Cancer Center, Gainesville, FL 32610, USA.
⁶ National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
⁷ University of Chicago, Department of Pathology, Chicago, IL 60637, USA.
⁸ GU Malignancies Branch, NCI, NIH, Bethesda, MD 20892, USA.
⁹ Molecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research, NIH, Frederick, MD 21702, USA.
¹⁰ National Institute of Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
¹¹ Ionis Pharmaceuticals, Carlsbad, CA 92010, USA.
¹² Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹³ Protein Characterization Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, MD 21702, USA.
¹⁴ 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.
¹⁵ 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.
¹⁶ Genome Modification Core, Laboratory Animal Sciences Program, Frederick National Lab for Cancer Research, Frederick, MD 21702, USA.
¹⁷ Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo 135-0063, Japan.
¹⁸ Dana Farber Cancer Institute, Boston, MA 02215, USA.
¹⁹ Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA. Electronic address: vassiliki.saloura@nih.gov.

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.

Keywords: CP: Cancer; CP: Immunology; SMYD3; antitumor immune response; head and neck cancer; interferon response.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

CCAAT-Enhancer-Binding Proteins
CD8-Positive T-Lymphocytes
Head and Neck Neoplasms* / drug therapy
Head and Neck Neoplasms* / genetics
Histone-Lysine N-Methyltransferase* / genetics
Humans
Interferon Type I*
Papillomavirus Infections*
Squamous Cell Carcinoma of Head and Neck* / drug therapy
Squamous Cell Carcinoma of Head and Neck* / genetics
Ubiquitin-Protein Ligases

Substances

CCAAT-Enhancer-Binding Proteins
Histone-Lysine N-Methyltransferase
Interferon Type I
SMYD3 protein, human
Ubiquitin-Protein Ligases
UHRF1 protein, human

Abstract

Publication types

MeSH terms

Substances

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