Department of Microbiology, Immunology, and Cancer Biology, The University of Virginia, Charlottesville, VA, 22908, USA.
Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA, 22908, USA.
Nat Commun. 2023 Apr 14;14(1):2122. 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.
靶向 DNA 甲基转移酶 1（DNMT1）具有免疫调节和抗肿瘤活性，尤其是与癌症免疫疗法联合使用时。在这里，我们探索了 DNMT1 在雌性小鼠肿瘤血管中的免疫调节功能。内皮细胞（ECs）中的 Dnmt1 缺失会损害肿瘤生长，同时启动细胞因子驱动的细胞粘附分子的表达和趋化因子的表达，这些趋化因子对于 CD8 T 细胞穿过血管的迁移至关重要；因此，免疫检查点阻断（ICB）的疗效得到增强。我们发现促血管生成因子 FGF2 促进 ERK 介导的 DNMT1 磷酸化和核转位，从而抑制 ECs 中趋化因子 Cxcl9/Cxcl10 的转录。在 ECs 中靶向 Dnmt1 会减少增殖，但会增加 Th1 趋化因子的产生和 CD8 T 细胞的渗出，表明 DNMT1 程序免疫性无反应性肿瘤血管。我们的研究与临床前观察结果一致，即药物破坏 DNMT1 可增强 ICB 的活性，但表明假定在癌细胞中靶向的表观遗传途径也在肿瘤血管中起作用。
