2. Academic Validation
  3. Priming a vascular-selective cytokine response permits CD8+ T-cell entry into tumors

Priming a vascular-selective cytokine response permits CD8+ T-cell entry into tumors

  • Nat Commun. 2023 Apr 14;14(1):2122. doi: 10.1038/s41467-023-37807-z.
Dae Joong Kim 1,  Swetha Anandh 1,  Jamie L Null 1,  Piotr Przanowski 2,  Sanchita Bhatnagar 3,  Pankaj Kumar 2,  Sarah E Shelton 4 5,  Erin E Grundy 6,  Katherine B Chiappinelli 6,  Roger D Kamm 4 7,  David A Barbie 5 8,  Andrew C Dudley 9 10
Affiliations

Affiliations

  • 1 Department of Microbiology, Immunology, and Cancer Biology, The University of Virginia, Charlottesville, VA, 22908, USA.
  • 2 Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA, 22908, USA.
  • 3 Medical Microbiology and Immunology, The University of California Davis, School of Medicine, Davis, CA, 95616, USA.
  • 4 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • 6 Department of Microbiology, Immunology and Tropical Medicine, The George Washington University Cancer Center, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
  • 7 Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • 8 Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • 9 Department of Microbiology, Immunology, and Cancer Biology, The University of Virginia, Charlottesville, VA, 22908, USA. acd2g@virginia.edu.
  • 10 UVA Comprehensive Cancer Center, The University of Virginia, Charlottesville, VA, USA. acd2g@virginia.edu.
PMID: 37055433 DOI: 10.1038/s41467-023-37807-z
Abstract

Targeting DNA Methyltransferase 1 (DNMT1) has immunomodulatory and anti-neoplastic activity, especially when paired with Cancer immunotherapies. Here we explore the immunoregulatory functions of DNMT1 in the tumor vasculature of female mice. DNMT1 deletion in endothelial cells (ECs) impairs tumor growth while priming expression of cytokine-driven cell adhesion molecules and chemokines important for CD8+ T-cell trafficking across the vasculature; consequently, the efficacy of Immune Checkpoint blockade (ICB) is enhanced. We find that the proangiogenic factor FGF2 promotes ERK-mediated DNMT1 phosphorylation and nuclear translocation to repress transcription of the chemokines CXCL9/Cxcl10 in ECs. Targeting DNMT1 in ECs reduces proliferation but augments Th1 chemokine production and extravasation of CD8+ T-cells, suggesting DNMT1 programs immunologically anergic tumor vasculature. Our study is in good accord with preclinical observations that pharmacologically disrupting DNMT1 enhances the activity of ICB but suggests an epigenetic pathway presumed to be targeted in Cancer cells is also operative in the tumor vasculature.

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