1. SMYD3 represses tumor-intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck.
- Author
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Nigam N, Bernard B, Sevilla S, Kim S, Dar MS, Tsai D, Robbins Y, Burkitt K, Sievers C, Allen CT, Bennett RL, Tettey TT, Carter B, Rinaldi L, Lingen MW, Sater H, Edmondson EF, Moshiri A, Saeed A, Cheng H, Luo X, Brennan K, Koparde V, Chen C, Das S, Andresson T, Abdelmaksoud A, Murali M, Sakata S, Takeuchi K, Chari R, Nakamura Y, Uppaluri R, Sunwoo JB, Van Waes C, Licht JD, Hager GL, and Saloura V
- Subjects
- Humans, CCAAT-Enhancer-Binding Proteins, CD8-Positive T-Lymphocytes, Ubiquitin-Protein Ligases, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms genetics, Histone-Lysine N-Methyltransferase genetics, Interferon Type I, Papillomavirus Infections, Squamous Cell Carcinoma of Head and Neck drug therapy, Squamous Cell Carcinoma of Head and Neck genetics
- 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., Competing Interests: Declaration of interests L.R. is currently an employee of Delfi Diagnostics in Baltimore, MD, USA. X.L. was an employee and shareholder of Ionis Pharmaceuticals in Carlsbad, CA, USA during the conduct of this study. Y.N. is employed as the president of the National Institutes of Biomedical Innovation, Health and Nutrition, and has 6% of stocks of OncoTherapy Science. J.L. has research support by Epizyme., (Published by Elsevier Inc.)- Published
- 2023
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