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

Author:

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

Karim,Baktiar

Allen, Clint T

Saloura, Vassiliki
Author Address

Thoracic and GI Malignancies Branch, National Cancer Institute, Bethesda, MD 20892, USA., Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD 20892, USA., Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 20892, USA., Center for Cancer Research Vaccine Branch Flow Cytometry Core, National Cancer Institute, Bethesda, MD 20892, USA., Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Bethesda, MD 20852, USA., Head and Neck Section, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20852, USA., Center for Immuno-Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20852, USA., Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA., Molecular Histopathology Laboratory, National Institutes of Health, Frederick, MD 21702, USA.,

Abstract:

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 160;vivo and provides insight into actionable mechanisms of resistance to improve the efficacy of Smyd3 ASOs and anti-PD-1 combination.

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