Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies
Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies
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DOI：
10.1158/2326-6066.cir-15-0036
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发表时间：
2015-11-01
影响因子：
10.1
通讯作者：
Ochoa, Augusto C.
中科院分区：
文献类型：
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作者：
Hossain, Fokhrul;Al-Khami, Amir A.;Ochoa, Augusto C.
髓源性抑制细胞（MDSC）通过抑制T细胞免疫以及促进恶性细胞增殖和迁移来促进肿瘤生长。阻断肿瘤中MDSC的治疗潜力受到其异质性、可塑性以及对多种化疗药物的抗性的限制。近期研究强调了能量代谢途径在免疫细胞分化和功能中的作用；然而，调节MDSC的代谢特征仍不清楚。我们旨在确定MDSC所使用的能量代谢途径，明确其对免疫抑制功能的影响，并测试抑制该途径是否能阻断MDSC并增强抗肿瘤治疗。利用几种小鼠肿瘤模型，我们发现肿瘤浸润性MDSC（T - MDSC）增加了脂肪酸摄取并激活了脂肪酸氧化（FAO）。这伴随着线粒体质量增加、关键的FAO酶上调以及耗氧率增加。对FAO的药物抑制阻断了T - MDSC中的免疫抑制途径和功能，并降低了其抑制性细胞因子的产生。单独抑制FAO以T细胞依赖的方式显著延缓了肿瘤生长，并增强了过继性T细胞疗法的抗肿瘤效果。此外，FAO抑制与低剂量化疗联合完全抑制了T - MDSC的免疫抑制作用，并诱导了显著的抗肿瘤效果。有趣的是，在外周血和肿瘤中的人类MDSC中也发现了脂肪酸摄取和FAO相关酶表达的类似增加。这些结果支持将FAO抑制作为一种阻断MDSC并增强多种癌症治疗的新方法进行测试的可能性。（C）2015美国癌症研究协会
Myeloid-derived suppressor cells (MDSC) promote tumor growth by inhibiting T-cell immunity and promoting malignant cell proliferation and migration. The therapeutic potential of blocking MDSC in tumors has been limited by their heterogeneity, plasticity, and resistance to various chemotherapy agents. Recent studies have highlighted the role of energy metabolic pathways in the differentiation and function of immune cells; however, the metabolic characteristics regulating MDSC remain unclear. We aimed to determine the energy metabolic pathway (s) used by MDSC, establish its impact on their immunosuppressive function, and test whether its inhibition blocks MDSC and enhances antitumor therapies. Using several murine tumor models, we found that tumor-infiltrating MDSC (T-MDSC) increased fatty acid uptake and activated fatty acid oxidation (FAO). This was accompanied by an increased mitochondrial mass, upregulation of key FAO enzymes, and increased oxygen consumption rate. Pharmacologic inhibition of FAO blocked immune inhibitory pathways and functions in T-MDSC and decreased their production of inhibitory cytokines. FAO inhibition alone significantly delayed tumor growth in a T-cell-dependent manner and enhanced the antitumor effect of adoptive T-cell therapy. Furthermore, FAO inhibition combined with low-dose chemotherapy completely inhibited T-MDSC immunosuppressive effects and induced a significant antitumor effect. Interestingly, a similar increase in fatty acid uptake and expression of FAO-related enzymes was found in human MDSC in peripheral blood and tumors. These results support the possibility of testing FAO inhibition as a novel approach to block MDSC and enhance various cancer therapies. (C) 2015 AACR.