한빛사논문
- 조회508
Dae Joong Kim1, Swetha Anandh1, Jamie L. Null1, Piotr Przanowski2, Sanchita Bhatnagar3, Pankaj Kumar2, Sarah E. Shelton4,5, Erin E. Grundy6, Katherine B. Chiappinelli6, Roger D. Kamm4,7, David A. Barbie5,8 & Andrew C. Dudley1,9
1Department of Microbiology, Immunology, and Cancer Biology, The University of Virginia, Charlottesville, VA 22908, USA.
2Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA 22908, USA.
3Medical Microbiology and Immunology, The University of California Davis, School of Medicine, Davis, CA 95616, USA.
4Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
5Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
6Department 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.
7Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
8Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
9UVA Comprehensive Cancer Center, The University of Virginia, Charlottesville, VA, USA.
Corresponding author : Correspondence to Andrew C. Dudley.
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.
논문정보
- Research article
- 2023년 04월 (BRIC 등록일 2023-04-28)
- 국외 연구진
- 생명과학 > 면역학
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