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

被引：10

作者：

Nigam, Nupur ^{[1
,2
]}

Bernard, Benjamin ^{[1
]}

Sevilla, Samantha ^{[2
,3
]}

Kim, Sohyoung ^{[4
]}

Dar, Mohd Saleem ^{[1
]}

Tsai, Daniel ^{[1
]}

Robbins, Yvette

Burkitt, Kyunghee

Sievers, Cem ^{[5
]}

Allen, Clint T. ^{[6
]}

Bennett, Richard L. ^{[6
]}

Tettey, Theophilus T. ^{[4
]}

Carter, Benjamin ^{[7
]}

Rinaldi, Lorenzo ^{[4
]}

Lingen, Mark W. ^{[8
]}

Sater, Houssein ^{[9
]}

Edmondson, Elijah F. ^{[10
]}

Moshiri, Arfa

Saeed, Abbas ^{[1
]}

Cheng, Hui ^{[11
]}

Luo, Xiaolin ^{[12
]}

Brennan, Kevin ^{[13
]}

Koparde, Vishal

Chen, Chen ^{[13
]}

Das, Sudipto ^{[14
]}

Andresson, Thorkell ^{[14
]}

Abdelmaksoud, Abdalla

Murali, Madhavi

Sakata, Seiji ^{[15
,16
]}

Takeuchi, Kengo ^{[15
,16
,17
]}

Chari, Raj ^{[18
]}

Nakamura, Yusuke ^{[19
]}

Uppaluri, Ravindra ^{[20
]}

Sunwoo, John B. ^{[18
]}

Van Waes, Carter

Licht, Jonathan D. ^{[6
]}

Hager, Gordon L. ^{[4
]}

Saloura, Vassiliki ^{[1
]}

机构：

[1] NCI, Thorac & GI Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[2] NCI, NIH, Ctr Canc Res, Collaborat Bioinformat Resource, Bethesda, MD 20892 USA

[3] Frederick Natl Lab Canc Res, Adv Biomed Computat Sci, Frederick, MD 21702 USA

[4] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA

[5] NIDCD, Translat Tumor Immunol Program, NIH, Bethesda, MD 20892 USA

[6] Univ Florida, Canc Ctr, Gainesville, FL 32610 USA

[7] NHLBI, NIH, Bethesda, MD 20892 USA

[8] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA

[9] NCI, GU Malignancies Branch, NIH, Bethesda, MD 20892 USA

[10] NIH, Frederick Natl Lab Canc Res, Mol Histopathol Lab, Frederick, MD 21702 USA

[11] NIH, Natl Inst Deafness & Other Commun Disorders, Bethesda, MD 20892 USA

[12] Ionis Pharmaceut, Carlsbad, CA 92010 USA

[13] Stanford Univ, Dept Otolaryngol Head & Neck Surg, Sch Med, Stanford, CA 94305 USA

[14] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Prot Characterizat Lab, Frederick, MD 21702 USA

[15] Japanese Fdn Canc Res, Canc Inst, Pathol Project Mol Targets, Tokyo 1350063, Japan

[16] Japanese Fdn Canc Res, Canc Inst, Div Pathol, Tokyo 1350063, Japan

[17] Japanese Fdn Canc Res, Canc Inst Hosp, Dept Pathol, Tokyo 1350063, Japan

[18] Frederick Natl Lab Canc Res, Lab Anim Sci Program, Genome Modificat Core, Frederick, MD 21702 USA

[19] Japanese Fdn Canc Res, Canc Precis Med Ctr, Tokyo 1350063, Japan

[20] Dana Farber Canc Inst, Boston, MA 02215 USA

来源：

CELL REPORTS | 2023年 / 42卷 / 07期

基金：

美国国家卫生研究院;

关键词：

HISTONE METHYLTRANSFERASE; HUMAN-PAPILLOMAVIRUS; LYSINE METHYLATION; DNA METHYLATION; GENE-EXPRESSION; TUDOR DOMAIN; CANCER; UHRF1; DNMT1; OVEREXPRESSION;

D O I：

10.1016/j.celrep.2023.112823

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 asso-ciated 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.

引用

页数：29

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