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 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<sup>+</sup> 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<sup>+</sup> T-cells, including neutrophil enrichment through the upregulation of <i>Cxcl2</i>, repression of <i>Cxcl9,</i> and defective antigen presentation. This study sheds light on the immunomodulatory functions of Smyd3 <i>in vivo</i> and provides insight into actionable mechanisms of resistance to improve the efficacy of Smyd3 ASOs and anti-PD-1 combination.
Authors
- Madhavi Murali (ORCID: https://orcid.org/0000-0003-0077-9256)
- Vassiliki Saloura (ORCID: https://orcid.org/0000-0002-9736-8578)
- Angel P. Huynh
- Andrew Sinkoe (ORCID: https://orcid.org/0000-0001-8311-1993)
- Sohyoung Kim (ORCID: https://orcid.org/0000-0002-6140-7918)
- Benjamin Bernard (ORCID: https://orcid.org/0000-0002-1199-7374)
- Abdalla Abdelmaksoud
- Marie K. Luff (ORCID: https://orcid.org/0000-0003-4137-3930)
- Baktiar O. Karim (ORCID: https://orcid.org/0000-0001-9604-9762)
- Clint Allen (ORCID: https://orcid.org/0000-0001-6586-5804)
- Yvette Robbins (ORCID: https://orcid.org/0000-0003-0940-3941)
- Mohd Saleem Dar (ORCID: https://orcid.org/0000-0003-4925-6819)
- Katherine McKinnon (ORCID: https://orcid.org/0000-0002-8281-3077)
- Daniel E Tsai
- Alexei Lovanov
- Xiaolin Luo (ORCID: https://orcid.org/0000-0003-3215-8112)
- Jawad Akhtar (ORCID: https://orcid.org/0000-0001-9554-8949)
Institutions
- National Institutes of Health (US)
- Ionis Pharmaceuticals (United States) (US)
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
Publication Details
- Journal
- iScience
- Published
- 2024-08-30
- DOI
- https://doi.org/10.1016/j.isci.2024.110854
- Citations
- 8
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.87
Funders
- U.S. Department of Health and Human Services
- National Institutes of Health
- National Cancer Institute