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

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. [Display omitted] •SMYD3 depletion derepresses type I IFN response and APM genes in HPV-negative HNSCC cells•SMYD3 represses immune genes through UHRF1, an H3K9me3-reader, and deposition of H4K20me3•Smyd3 ASOs increase CD8+ T cell influx and sensitize MOC1 tumors to anti-PD-1 therapy•SMYD3 mRNA levels predict response to neoadjuvant pembrolizumab in HPV-negative HNSCC Nigam et al. show that SMYD3 depletion induces type I IFN response and APM genes in HPV-negative HNSCC cells. SMYD3 represses immune-related genes through direct transcriptional regulation of UHRF1, an H3K9me3-reader that recruits DNMT1A, and deposition of H4K20me3. SMYD3 is a rational target to overcome anti-PD-1 resistance in HPV-negative HNSCC.