BACKGROUND Increased numbers of myeloid-derived suppressor cells (MDSCs) are positively correlated with poor prognosis and reduced survivals of cancer patients. They play central roles in tumor immune evasion and tumor metastasis. However, limited data are available on phenotypic/transcriptomic characteristics of the different MDSCs subsets in cancer. These cells include immature (I-MDSCs), monocytic (M-MDSCs), and polymorphonuclear/granulocytic (PMN-MDSCs). METHODS Phenotypic characterization of myeloid subsets from 27 colorectal cancer (CRC) patients was assessed by flow cytometric analyses. RNA-sequencing of sorted I-MDSCs, PMN-MDSCs, and antigen-presenting cells (APCs) was also performed. RESULTS We found that the levels of I-MDSCs and PMN-MDSCs were increased in tumor tissues (TT), compared with normal tissues (NT) in colorectal cancer. Our functional annotation analyses showed that genes associated with histone deacetylase (HDAC) activation- and DNA methylation-mediated transcriptional silencing were upregulated, and histone acetyl transferase (HAT)-related genes were downregulated in tumor-infiltrating I-MDSCs. Moreover, pathways implicated in cell trafficking and immune suppression, including Wnt, interleukin-6 (IL-6), and mitogen-activated protein kinase (MAPK) signaling, were upregulated in I-MDSCs. Notably, PMN-MDSCs showed downregulation in genes related to DNA methylation and HDAC binding. Using an ex vivo model, we found that inhibition of HDAC activation or neutralization of IL-6 in CRC tumor tissues downregulates the expression of genes associated with immunosuppression and myeloid cell chemotaxis, confirming the importance of HDAC activation and IL-6 signaling pathway in MDSC function and chemotaxis. CONCLUSIONS This study provides novel insights into the epigenetic regulations and other molecular pathways in different myeloid cell subsets within the CRC tumor microenvironment (TME), giving opportunities to potential targets for therapeutic benefits.

中文翻译：

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转录组学分析揭示了 DNA 甲基化和组蛋白修饰在结直肠癌肿瘤浸润性髓源性抑制细胞亚群中的作用。

背景 髓源性抑制细胞 (MDSC) 数量的增加与癌症患者的预后不良和存活率降低呈正相关。它们在肿瘤免疫逃避和肿瘤转移中发挥核心作用。然而，关于癌症中不同 MDSC 亚群的表型/转录组特征的数据有限。这些细胞包括未成熟的 (I-MDSCs)、单核细胞 (M-MDSCs) 和多形核/粒细胞 (PMN-MDSCs)。方法通过流式细胞术分析评估来自 27 名结直肠癌 (CRC) 患者的骨髓亚群的表型特征。还对分选的 I-MDSC、PMN-MDSC 和抗原呈递细胞 (APC) 进行了 RNA 测序。结果 我们发现，与结直肠癌中的正常组织 (NT) 相比，肿瘤组织 (TT) 中 I-MDSCs 和 PMN-MDSCs 的水平升高。我们的功能注释分析表明，与组蛋白去乙酰化酶 (HDAC) 激活和 DNA 甲基化介导的转录沉默相关的基因被上调，而组蛋白乙酰转移酶 (HAT) 相关基因在肿瘤浸润性 I-MDSC 中被下调。此外，与细胞运输和免疫抑制有关的通路，包括 Wnt、白细胞介素 6 (IL-6) 和丝裂原活化蛋白激酶 (MAPK) 信号通路，在 I-MDSC 中被上调。值得注意的是，PMN-MDSCs 在与 DNA 甲基化和 HDAC 结合相关的基因中表现出下调。使用离体模型，我们发现在 CRC 肿瘤组织中抑制 HDAC 激活或中和 IL-6 会下调与免疫抑制和骨髓细胞趋化性相关的基因的表达，确认 HDAC 激活和 IL-6 信号通路在 MDSC 功能和趋化性中的重要性。结论 本研究为 CRC 肿瘤微环境 (TME) 内不同骨髓细胞亚群的表观遗传调控和其他分子途径提供了新的见解，为潜在的治疗目标提供了机会。