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

• Published in: Nature communications Vol. 14; no. 1; pp. 2122 - 16
• Main Authors: Kim, Dae Joong, Anandh, Swetha, Null, Jamie L., Przanowski, Piotr, Bhatnagar, Sanchita, Kumar, Pankaj, Shelton, Sarah E., Grundy, Erin E., Chiappinelli, Katherine B., Kamm, Roger D., Barbie, David A., Dudley, Andrew C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.04.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/31; 13/51; 14/63; 38; 38/15; 38/77; 59; 631/250/98; 631/67/327; 64; 64/60; 692/4028/67/580; 96/109; Anergy; Animals; Cancer; Cancer immunotherapy; CD8 antigen; CD8-Positive T-Lymphocytes; Cell adhesion; Cell adhesion molecules; Cell proliferation; Chemokine CXCL10 - metabolism; Chemokines; Clonal deletion; CXCL10 protein; Cytokines; Cytokines - metabolism; Deletion; Deoxyribonucleic acid; DNA; DNA methyltransferase; DNMT1 protein; Endothelial cells; Endothelial Cells - metabolism; Epigenetics; Extravasation; Female; Fibroblast growth factor 2; Humanities and Social Sciences; Immune checkpoint inhibitors; Immunomodulation; Immunoregulation; Lymphocytes; Lymphocytes T; Metastases; Mice; multidisciplinary; Neoplasms - metabolism; Neoplasms - therapy; Nuclear transport; Phosphorylation; Priming; Science; Science (multidisciplinary); Translocation; Tumors; Virus Internalization
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37807-z

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. It has been reported that inhibition of the epigenetic regulator DNA methyltransferase 1 (DNMT1) is associated with improved response to immune checkpoint blockade (ICB). Here the authors show that conditional deletion of Dnmt1 in endothelial cells is sufficient to promote T cell infiltration, reduce tumor growth and enhance ICB response in preclinical models.