Abstract：
Mesenchymal stromal cells (MSCs) are commonly known for their immune-suppressive abilities. However, our group provided evidence that it is possible to convert MSCs into potent antigen presenting cells (APCs) using either genetic engineering or pharmacological means. Given the capacity of UM171a to trigger APC-like function in MSCs, and the recent finding that this drug may modulate the epigenome by inhibiting the lysine-specific demethylase 1 (LSD1), we explored whether the direct pharmacological inhibition of LSD1 could instill APC-like functions in MSCs akin to UM171a. The treatment of MSCs with the LSD1 inhibitor tranylcypromine (TC) elicits a double-stranded (ds)RNA stress response along with its associated responsive elements, including pattern recognition receptors (PRRs), Type-I interferon (IFN), and IFN-stimulated genes (ISGs). The net outcome culminates in the enhanced expression of H2-Kb, and an increased stability of the cell surface peptide: MHCI complexes. As a result, TC-treated MSCs stimulate CD8 T-cell activation efficiently, and elicit potent anti-tumoral responses against the EG.7 T-cell lymphoma in the context of prophylactic vaccination. Altogether, our findings reveal a new pharmacological protocol whereby targeting LSD1 in MSCs elicits APC-like capabilities that could be easily exploited in the design of future MSC-based anti-cancer vaccines.
摘要：
间充质基质细胞(MSC)通常以其免疫抑制能力而闻名。然而,我们小组提供的证据表明,利用基因工程或药理学手段将MSCs转化为有效的抗原呈递细胞(APC)是可能的.鉴于UM171a在MSC中触发APC样功能的能力，以及最近的发现，这种药物可能通过抑制赖氨酸特异性去甲基酶1（LSD1）来调节表观基因组，我们探讨了LSD1的直接药理学抑制是否可以在MSCs中灌输类似于UM171a的APC样功能.用LSD1抑制剂tranylcypromine（TC）处理MSC引起双链（ds）RNA应激反应及其相关的响应元件，包括模式识别受体（PRR），I型干扰素(IFN),和IFN刺激基因(ISGs)。最终结果是H2-Kb的表达增强，和增加的细胞表面肽:MHCI复合物的稳定性。因此,TC处理的MSCs有效刺激CD8T细胞活化，并在预防性疫苗接种的情况下引发针对EG.7T细胞淋巴瘤的有效抗肿瘤反应。总之,我们的研究结果揭示了一种新的药理学方案,通过该方案,在MSCs中靶向LSD1可引发APC样功能,该功能可在未来基于MSC的抗癌疫苗的设计中轻松利用.
