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

Dae Joong Kim, Swetha Anandh, Jamie L. Null, Piotr Przanowski, Sanchita Bhatnagar, Pankaj Kumar, Sarah E. Shelton, Erin E. Grundy, Katherine B. Chiappinelli, Roger D. Kamm, David A. Barbie and Andrew C. Dudley ()
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Dae Joong Kim: The University of Virginia
Swetha Anandh: The University of Virginia
Jamie L. Null: The University of Virginia
Piotr Przanowski: The University of Virginia
Sanchita Bhatnagar: School of Medicine
Pankaj Kumar: The University of Virginia
Sarah E. Shelton: Massachusetts Institute of Technology
Erin E. Grundy: The George Washington University Cancer Center, The George Washington University School of Medicine and Health Sciences
Katherine B. Chiappinelli: The George Washington University Cancer Center, The George Washington University School of Medicine and Health Sciences
Roger D. Kamm: Massachusetts Institute of Technology
David A. Barbie: Dana-Farber Cancer Institute
Andrew C. Dudley: The University of Virginia

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37807-z

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