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

Targeting DNA methyltransferase 1 (DNMT1) has immunomodulatory and anti-neoplastic activity, especially when paired with cancer immunotherapies. Here we explored the immunoregulatory functions of DNMT1 in the tumor vasculature. Dnmt1 deletion in endothelial cells (ECs) impairs tumor growth and metastatic seeding 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. Tumor ECs reduced in IFNg response genes are enriched in cell cycle effectors, including Dnmt1, indicating mitotic ECs suppress anti-tumor immune responses. Targeting Dnmt1 in ECs reduces proliferation and augments adhesion and diapedesis 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. Overall design: Overall design: "Tumor associated endothelial cells or mammary gland endothelial cells were isolated (from pooled orthotopically implanted E0771 mammary tumors or normal mammary glands) using FACS for CD45-/CD31+ populations."