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

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.

SUBMITTER: Nigam N 

PROVIDER: S-EPMC10407766 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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

Nigam Nupur N   Bernard Benjamin B   Sevilla Samantha S   Kim Sohyoung S   Dar Mohd Saleem MS   Tsai Daniel D   Robbins Yvette Y   Burkitt Kyunghee K   Sievers Cem C   Allen Clint T CT   Bennett Richard L RL   Tettey Theophilus T TT   Carter Benjamin B   Rinaldi Lorenzo L   Lingen Mark W MW   Sater Houssein H   Edmondson Elijah F EF   Moshiri Arfa A   Saeed Abbas A   Cheng Hui H   Luo Xiaolin X   Brennan Kevin K   Koparde Vishal V   Chen Chen C   Das Sudipto S   Andresson Thorkell T   Abdelmaksoud Abdalla A   Murali Madhavi M   Sakata Seiji S   Takeuchi Kengo K   Chari Raj R   Nakamura Yusuke Y   Uppaluri Ravindra R   Sunwoo John B JB   Van Waes Carter C   Licht Jonathan D JD   Hager Gordon L GL   Saloura Vassiliki V  

Cell reports 20230717 7

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 tran  ...[more]

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