The use of immunotherapy to treat patients with myelodysplastic syndromes (MDS) shows promise but is limited by our incomplete understanding of the immunologic milieu. In solid tumors, CD141Hi conventional dendritic cells (CD141Hi cDCs) are necessary for antitumor immunosurveillance and the response to immunotherapy. Here, we found that CD141Hi cDCs are reduced in MDS bone marrow and based on the premise established in solid tumors, we hypothesized that reduced numbers of CD141Hi cDCs are associated with inferior overall survival in MDS patients. We found that MDS patients with reduced numbers of CD141Hi cDCs, but not other DC populations, showed reduced overall survival. To examine the basis for reduction in CD141Hi cDCs, we found fewer numbers of progenitors committed to DC differentiation in the MDS bone marrow and these progenitors expressed lower levels of interferon regulatory factor-8 (IRF8), a master regulator of CD141Hi cDC differentiation. To rescue impaired CD141Hi cDC differentiation, we used pharmacologic inhibition of lysine-specific demethylase 1A (LSD1) to promote CD141Hi cDC differentiation by MDS progenitors. These data reveal a previously unrecognized element of the MDS immunologic milieu. Epigenetic regulation of CD141Hi cDC differentiation offers an intriguing opportunity for intervention and a potential adjunct to immunotherapy for patients with MDS.

中文翻译：

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MDS 祖细胞中 LSD1 的抑制可恢复 CD141Hi 常规树突状细胞的分化。

使用免疫疗法治疗骨髓增生异常综合征（MDS）患者显示出希望，但由于我们对免疫环境的不完全了解而受到限制。在实体瘤中，CD141Hi 常规树突状细胞 (CD141Hi cDC) 对于抗肿瘤免疫监视和免疫治疗反应是必需的。在这里，我们发现MDS骨髓中CD141Hi cDC减少，并且基于在实体瘤中建立的前提，我们假设CD141Hi cDC数量减少与MDS患者总生存率较差相关。我们发现，CD141Hi cDC 数量减少的 MDS 患者（而非其他 DC 群体）表现出总生存率降低。为了检查 CD141Hi cDC 减少的基础，我们发现 MDS 骨髓中致力于 DC 分化的祖细胞数量较少，并且这些祖细胞表达较低水平的干扰素调节因子 8 (IRF8)，这是 CD141Hi cDC 分化的主要调节因子。为了挽救受损的 CD141Hi cDC 分化，我们使用赖氨酸特异性去甲基酶 1A (LSD1) 的药理学抑制来促进 MDS 祖细胞的 CD141Hi cDC 分化。这些数据揭示了 MDS 免疫环境中以前未被识别的元素。CD141Hi cDC 分化的表观遗传调控为 MDS 患者的干预和免疫治疗的潜在辅助提供了一个有趣的机会。