Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia.
Georgia Cancer Center, Medical College of Georgia, Augusta, Georgia.
Cancer Res. 2020 Aug 1;80(15):3145-3156. doi: 10.1158/0008-5472.CAN-19-3670. Epub 2020 Jun 17.
Although accumulation of myeloid-derived suppressor cells (MDSC) is a hallmark of cancer, the underlying mechanism of this accumulation within the tumor microenvironment remains incompletely understood. We report here that TNFα-RIP1-mediated necroptosis regulates accumulation of MDSCs. In tumor-bearing mice, pharmacologic inhibition of DNMT with the DNA methyltransferease inhibitor decitabine (DAC) decreased MDSC accumulation and increased activation of antigen-specific cytotoxic T lymphocytes. DAC-induced decreases in MDSC accumulation correlated with increased expression of the myeloid cell lineage-specific transcription factor IRF8 in MDSCs. However, DAC also suppressed MDSC-like cell accumulation in IRF8-deficient mice, indicating that DNA methylation may regulate MDSC survival through an IRF8-independent mechanism. Instead, DAC decreased MDSC accumulation by increasing cell death via disrupting DNA methylation of RIP1-dependent targets of necroptosis. Genome-wide DNA bisulfite sequencing revealed that the promoter was hypermethylated in tumor-induced MDSCs . DAC treatment dramatically increased TNFα levels in MDSC , and neutralizing TNFα significantly increased MDSC accumulation and tumor growth in tumor-bearing mice . Recombinant TNFα induced MDSC cell death in a dose- and RIP1-dependent manner. IL6 was abundantly expressed in MDSCs in tumor-bearing mice and patients with human colorectal cancer. , IL6 treatment of MDSC-like cells activated STAT3, increased expression of DNMT1 and DNMT3b, and enhanced survival. Overall, our findings reveal that MDSCs establish a STAT3-DNMT epigenetic axis, regulated by autocrine IL6, to silence TNFα expression. This results in decreased TNFα-induced and RIP1-dependent necroptosis to sustain survival and accumulation. SIGNIFICANCE: These findings demonstrate that targeting IL6 expression or function represent potentially effective approaches to suppress MDSC survival and accumulation in the tumor microenvironment.
虽然髓源性抑制细胞（MDSC）的积累是癌症的一个标志，但这种在肿瘤微环境中的积累的潜在机制仍不完全清楚。我们在这里报告，TNFα-RIP1 介导的坏死性凋亡调节 MDSC 的积累。在荷瘤小鼠中，用 DNA 甲基转移酶抑制剂地西他滨（DAC）抑制 DNMT 的药理作用降低了 MDSC 的积累，并增加了抗原特异性细胞毒性 T 淋巴细胞的激活。DAC 诱导的 MDSC 积累减少与 MDSC 中髓系细胞谱系特异性转录因子 IRF8 的表达增加相关。然而，DAC 也抑制了 IRF8 缺陷型小鼠中 MDSC 样细胞的积累，表明 DNA 甲基化可能通过独立于 IRF8 的机制调节 MDSC 的存活。相反，DAC 通过破坏坏死性凋亡的 RIP1 依赖性靶标的 DNA 甲基化来增加细胞死亡，从而减少 MDSC 的积累。全基因组 DNA 亚硫酸氢盐测序显示，在肿瘤诱导的 MDSC 中， 启动子呈高甲基化。DAC 处理显著增加了 MDSC 中的 TNFα 水平，中和 TNFα 显著增加了荷瘤小鼠中的 MDSC 积累和肿瘤生长。重组 TNFα 以剂量和 RIP1 依赖性的方式诱导 MDSC 细胞死亡。IL6 在荷瘤小鼠和人类结直肠癌患者的 MDSC 中大量表达。IL6 处理 MDSC 样细胞激活了 STAT3，增加了 DNMT1 和 DNMT3b 的表达，并增强了存活。总的来说，我们的发现表明 MDSC 建立了一个 STAT3-DNMT 表观遗传轴，受自分泌 IL6 调控，沉默 TNFα 表达。这导致减少 TNFα 诱导和 RIP1 依赖性坏死性凋亡以维持存活和积累。意义：这些发现表明，靶向 IL6 表达或功能可能是抑制肿瘤微环境中 MDSC 存活和积累的有效方法。
