Low-dose decitabine modulates myeloid-derived suppressor cell fitness via LKB1 in immune thrombocytopenia
Low-dose decitabine modulates myeloid-derived suppressor cell fitness via LKB1 in immune thrombocytopenia
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DOI：
10.1182/blood.2022016029
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发表时间：
2022-12-29
期刊：
影响因子：
20.3
通讯作者：
Hou, Yu
中科院分区：
文献类型：
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作者：
Ni, Xiaofei;Wang, Lingjun;Hou, Yu
骨髓源性抑制细胞（MDSC）是异质性的未成熟细胞，是获得性免疫的天然抑制剂。MDSC的代谢适应性是其对效应T细胞的抑制活性的基础。我们以前的研究表明，与健康对照组相比，免疫性血小板减少症（ITP）患者的MDSC数量和抑制功能受损。在这项研究中，我们分析了地西他滨对ITP患者MDSC的体外和体内影响。我们发现，低剂量地西他滨促进MDSCs的生成，并增强其有氧代谢和免疫抑制功能。ITP患者MDSC中肝激酶1（LKB 1）的表达较低，经地西他滨治疗后，LKB 1的表达得到纠正。LKB1短发夹RNA（shRNA）转染有效地阻断了MDSCs的功能，几乎抵消了地西他滨对受损MDSCs的增强作用。随后，将抗CD61免疫致敏的脾细胞转移到严重联合免疫缺陷（SCID）小鼠中以在鼠模型中诱导ITP。与磷酸盐缓冲盐水调节的MDSC相比，地西他滨调节的MDSC的被动转移显著提高了血小板计数。然而，当将LKB1 shRNA转染的MDSC转移到SCID小鼠中时，地西他滨减轻血小板减少症的治疗作用被淬灭。结论：MDSC有氧代谢受损参与了ITP的发病机制，地西他滨通过调节MDSC的有氧代谢，改善其免疫抑制功能。这为ITP患者低剂量地西他滨引起的持续缓解提供了可能的机制。
Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature cells and natural inhibitors of adaptive immunity. Metabolic fitness of MDSCs is fundamental for its suppressive activity toward effector T cells. Our previous studies showed that the number and inhibitory function of MDSCs were impaired in patients with immune thrombocytopenia (ITP) compared with healthy controls. In this study, we analyzed the effects of decitabine on MDSCs from patients with ITP, both in vitro and in vivo. We found that low-dose decitabine promoted the generation of MDSCs and enhanced their aerobic metabolism and immunosuppressive functions. Lower expression of liver kinase 1 (LKB1) was found in MDSCs from patients with ITP, which was corrected by decitabine therapy. LKB1 short hairpin RNA (shRNA) transfection effectively blocked the function of MDSCs and almost offset the enhanced effect of decitabine on impaired MDSCs. Subsequently, anti-CD61 immune -sensitized splenocytes were transferred into severe combined immunodeficient (SCID) mice to induce ITP in murine models. Passive transfer of decitabine-modulated MDSCs significantly raised platelet counts compared with that of phosphate buffered saline-modulated MDSCs. However, when LKB1 shRNA-transfected MDSCs were transferred into SCID mice, the therapeutic effect of decitabine in alleviating thrombocytopenia was quenched. In conclusion, our study suggests that the impaired aerobic metabolism of MDSCs is involved in the pathogenesis of ITP, and the modulatory effect of decitabine on MDSC metabolism contributes to the improvement of its immunosuppressive function. This provides a possible mechanism for sustained remission elicited by low-dose decitabine in patients with ITP.