학술논문
SMYD3 represses tumor-intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck
Document Type
article
Author
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
Source
Cell Reports, Vol 42, Iss 7, Pp 112823- (2023)
Subject
Language
English
ISSN
2211-1247
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.