Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Cancer Res. 2019 Oct 1;79(19):5034-5047. doi: 10.1158/0008-5472.CAN-19-0880. Epub 2019 Aug 13.
Myeloid-derived suppressor cells (MDSC) represent a primary mechanism of immune evasion in tumors and have emerged as a major obstacle for cancer immunotherapy. The immunoinhibitory activity of MDSC is tightly regulated by the tumor microenvironment and occurs through mechanistic mediators that remain unclear. Here, we elucidated the intrinsic interaction between the expression of AMP-activated protein kinase alpha (AMPKα) and the immunoregulatory activity of MDSC in tumors. AMPKα signaling was increased in tumor-MDSC from tumor-bearing mice and patients with ovarian cancer. Transcription of the Ampkα1-coding gene, , in tumor-MDSC was induced by cancer cell-derived granulocyte-monocyte colony-stimulating factor (GM-CSF) and occurred in a Stat5-dependent manner. Conditional deletion of in myeloid cells, or therapeutic inhibition of Ampkα in tumor-bearing mice, delayed tumor growth, inhibited the immunosuppressive potential of MDSC, triggered antitumor CD8 T-cell immunity, and boosted the efficacy of T-cell immunotherapy. Complementarily, therapeutic stimulation of AMPKα signaling intrinsically promoted MDSC immunoregulatory activity. In addition, deletion antagonized the differentiation of monocytic-MDSC (M-MDSC) to macrophages and re-routed M-MDSC, but not granulocytic-MDSC (PMN-MDSC), into cells that elicited direct antitumor cytotoxic effects through nitric oxide synthase 2-mediated actions. Thus, our results demonstrate the primary role of AMPKα1 in the immunosuppressive effects induced by tumor-MDSC and support the therapeutic use of AMPK inhibitors to overcome MDSC-induced T-cell dysfunction in cancer. SIGNIFICANCE: AMPKα1 regulates the immunosuppressive activity and differentiation of tumor-MDSC, suggesting AMPK inhibition as a potential therapeutic strategy to restore protective myelopoiesis in cancer.
髓源抑制性细胞 (MDSC) 是肿瘤免疫逃逸的主要机制，也是癌症免疫治疗的主要障碍。MDSC 的免疫抑制活性受肿瘤微环境的严格调控，其发生机制尚不清楚。在这里，我们阐明了 AMP 激活蛋白激酶α (AMPKα) 的表达与肿瘤中 MDSC 的免疫调节活性之间的内在相互作用。肿瘤中 MDSC 的 AMPKα 信号增强来自荷瘤小鼠和卵巢癌患者的肿瘤-MDSC。肿瘤-MDSC 中转录 Ampkα1 编码基因 受癌细胞衍生的粒细胞-单核细胞集落刺激因子 (GM-CSF) 诱导，并以 Stat5 依赖的方式发生。在髓细胞中条件性缺失 ，或在荷瘤小鼠中治疗性抑制 Ampkα，可延迟肿瘤生长、抑制 MDSC 的免疫抑制潜能、触发抗肿瘤 CD8 T 细胞免疫、并增强 T 细胞免疫治疗的疗效。此外，AMPKα 信号的治疗性刺激内在地促进了 MDSC 的免疫调节活性。此外， 缺失拮抗单核细胞来源的 MDSC (M-MDSC) 向巨噬细胞的分化，并通过诱导型一氧化氮合酶 2 介导的作用将 M-MDSC 重新定向为具有直接抗肿瘤细胞毒性作用的细胞。因此，我们的研究结果表明 AMPKα1 在肿瘤-MDSC 诱导的免疫抑制作用中起主要作用，并支持 AMPK 抑制剂的治疗用途，以克服癌症中 MDSC 诱导的 T 细胞功能障碍。意义：AMPKα1 调节肿瘤-MDSC 的免疫抑制活性和分化，提示 AMPK 抑制可能是恢复癌症保护性髓系生成的潜在治疗策略。
