Smyd3-mediated immuno-modulation in HPV-negative head and neck squamous cell carcinoma mouse models

SET and MYND-domain containing protein 3 (SMYD3) mediates epigenetic repression of type I IFN response genes in human papillomavirus (HPV)-negative HNSCC cells, and Smyd3 depletion using anti-sense oligonucleotides (ASOs) increases the sensitivity of syngeneic mouse oral carcinoma (MOC1) models to a...

Full description

Saved in:

Bibliographic Details
Published in:	iScience Vol. 27; no. 9; p. 110854
Main Authors:	Tsai, Daniel E., Lovanov, Alexei, Abdelmaksoud, Abdalla, Akhtar, Jawad, Dar, Mohd Saleem, Luff, Marie, McKinnon, Katherine, Kim, Sohyoung, Robbins, Yvette, Huynh, Angel, Murali, Madhavi, Bernard, Benjamin, Sinkoe, Andrew, Luo, Xiaolin, B, Karim, Allen, Clint T., Saloura, Vassiliki
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 20-09-2024 Elsevier
Subjects:	Cell biology Immunology Microenvironment Cell biology Immunology Microenvironment
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	SET and MYND-domain containing protein 3 (SMYD3) mediates epigenetic repression of type I IFN response genes in human papillomavirus (HPV)-negative HNSCC cells, and Smyd3 depletion using anti-sense oligonucleotides (ASOs) increases the sensitivity of syngeneic mouse oral carcinoma (MOC1) models to anti-PD-1 therapy. In this study, we utilized single-cell RNA-seq of MOC1 tumors treated with Smyd3 ASOs and found enrichment of type I IFN response pathways in cancer cells, a shift of CD8+ T-cells toward an activated/memory phenotype, and a shift of neutrophils toward an anti-tumorigenic phenotype. Mechanisms of resistance to the Smyd3 ASO and anti-PD-1 combination were derived from cancer cells, macrophages, and CD8+ T-cells, including neutrophil enrichment through the upregulation of Cxcl2, repression of Cxcl9, and defective antigen presentation. This study sheds light on the immunomodulatory functions of Smyd3 in vivo and provides insight into actionable mechanisms of resistance to improve the efficacy of Smyd3 ASOs and anti-PD-1 combination. [Display omitted] •Smyd3 ASOs reinvigorate CD8+ T-cells and promote anti-tumor neutrophils in vivo•Smyd3 ASOs may promote a Treg and M2 macrophage phenotype in vivo•Smyd3 ASO and anti-PD-1 combination induces IFN gene signatures in MOC1 tumors•Resistance to Smyd3 ASOs and anti-PD-1 stems from different cell types of the TME Immunology; Microenvironment; Cell biology
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Lead contact
ISSN:	2589-0042 2589-0042
DOI:	10.1016/j.isci.2024.110854