Scaffolding LSD1 Inhibitors Impair NK Cell Metabolism and Cytotoxic Function Through Depletion of Glutathione.
Scaffolding LSD1 Inhibitors Impair NK Cell Metabolism and Cytotoxic Function Through Depletion of Glutathione.
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DOI：
10.3389/fimmu.2020.02196
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发表时间：
2020
影响因子：
7.3
通讯作者：
Chandra J
中科院分区：
文献类型：
--
作者：
Bailey CP;Figueroa M;Gangadharan A;Lee DA;Chandra J
细胞疗法，如嵌合抗原受体（CAR）T细胞和NK细胞是治疗癌症和其他疾病的尖端方法。人们对优化药物治疗方案以最好地与新兴细胞疗法一起工作非常感兴趣，例如靶向表观遗传酶以刺激免疫细胞对肿瘤细胞的识别。在此，我们揭示了组蛋白去甲基化酶LSD 1的新机制，以及针对LSD 1独特结构域的各种抑制剂，在NK细胞生长用于细胞治疗的功能中。催化抑制剂（反苯环丙胺和结构衍生物GSK LSD 1和RN-1）可以不可逆地阻断LSD 1的脱甲基酶活性，而支架抑制剂（SP-2509和临床继任者SP-2577，也称为seclidemstat）破坏包括LSD 1的表观遗传复合物。LSD 1抑制剂与细胞治疗输注和免疫检查点阻断的相关组合在临床前实体瘤模型中显示出疗效，加强了了解这些药物如何影响T细胞和NK细胞的需要。我们发现，支架LSD 1抑制剂可以有效减少NK细胞的氧化磷酸化和糖酵解，较高剂量会诱导线粒体活性氧和抗氧化剂谷胱甘肽的消耗。与催化剂相比，这些效应对于支架抑制剂是独特的，对于NK细胞与T细胞相比，重要的是，可以完全消除NK细胞的裂解能力。补充生物学可达到水平的谷胱甘肽可挽救NK细胞的细胞溶解功能，但不能挽救NK细胞的代谢。我们的研究结果表明，补充谷胱甘肽可以逆转使用seclidemstat治疗的患者的NK细胞活性抑制。
Cell therapies such as chimeric-antigen receptor (CAR) T-cells and NK cells are cutting-edge methods for treating cancer and other diseases. There is high interest in optimizing drug treatment regimens to best work together with emerging cell therapies, such as targeting epigenetic enzymes to stimulate recognition of tumor cells by immune cells. Herein, we uncover new mechanisms of the histone demethylase LSD1, and various inhibitors targeting unique domains of LSD1, in the function of NK cells grown for cell therapy. Catalytic inhibitors (tranylcypromine and the structural derivatives GSK LSD1 and RN-1) can irreversibly block the demethylase activity of LSD1, while scaffolding inhibitors (SP-2509 and clinical successor SP-2577, also known as seclidemstat) disrupt epigenetic complexes that include LSD1. Relevant combinations of LSD1 inhibitors with cell therapy infusions and immune checkpoint blockade have shown efficacy in pre-clinical solid tumor models, reinforcing a need to understand how these drugs would impact T- and NK cells. We find that scaffolding LSD1 inhibitors potently reduce oxidative phosphorylation and glycolysis of NK cells, and higher doses induce mitochondrial reactive oxygen species and depletion of the antioxidant glutathione. These effects are unique to scaffolding inhibitors compared to catalytic, to NK cells compared to T-cells, and importantly, can fully ablate the lytic capacity of NK cells. Supplementation with biologically achievable levels of glutathione rescues NK cell cytolytic function but not NK cell metabolism. Our results suggest glutathione supplementation may reverse NK cell activity suppression in patients treated with seclidemstat.
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