The class I/IV HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy
The class I/IV HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy
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DOI：
10.1007/s00262-017-2091-y
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发表时间：
2018-03-01
影响因子：
5.8
通讯作者：
Christensen, James G.
中科院分区：
文献类型：
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作者：
Briere, David;Sudhakar, Niranjan;Christensen, James G.
检查点抑制剂疗法已经导致包括非小细胞肺癌（NSCLC）在内的几种癌症的重大治疗进展。尽管如此，仍有相当比例的患者没有反应或产生耐药性。潜在的耐药机制包括缺乏程序性死亡配体1（PD-L1）的表达，呈递肿瘤抗原的能力降低，以及存在免疫抑制性肿瘤微环境。Mocetinostat是I/IV类组蛋白脱乙酰酶（HDAC）的光谱选择性抑制剂，HDAC是涉及肿瘤和免疫细胞中免疫调节基因的表观遗传沉默的蛋白质家族。Mocetinostat在体外上调一组NSCLC细胞系中的PD-L1和抗原呈递基因，包括I类和II类人类白细胞抗原（HLA）家族成员。Mocetinostat靶基因启动子被I类HDAC占据，并在mocetinostat处理后表现出增加的活性组蛋白标记。Mocetinostat与干扰素γ（IFN-γ）协同调节II类反式激活因子（CIITA），这是II类HLA基因表达的主要调节因子。在同基因肿瘤模型中，mocetinostat减少了肿瘤内T调节细胞（TCRs）和潜在的髓源性抑制细胞（MDSC）群体，并增加了肿瘤内CD 8+群体。在离体测定中，患者来源的、莫西替司他处理的Tclase也显示出FOXP 3和HELIOS的显著下调。在两种同基因肿瘤模型中，与单独治疗相比，mocetinostat和鼠PD-L1抗体拮抗剂的组合显示出增加的抗肿瘤活性。总之，这些数据提供了证据，表明mocetinostat调节肿瘤细胞中的免疫相关基因以及肿瘤微环境中的免疫细胞类型，并增强检查点抑制剂治疗。
Checkpoint inhibitor therapy has led to major treatment advances for several cancers including non-small cell lung cancer (NSCLC). Despite this, a significant percentage of patients do not respond or develop resistance. Potential mechanisms of resistance include lack of expression of programmed death ligand 1 (PD-L1), decreased capacity to present tumor antigens, and the presence of an immunosuppressive tumor microenvironment. Mocetinostat is a spectrum-selective inhibitor of class I/IV histone deacetylases (HDACs), a family of proteins implicated in epigenetic silencing of immune regulatory genes in tumor and immune cells. Mocetinostat upregulated PD-L1 and antigen presentation genes including class I and II human leukocyte antigen (HLA) family members in a panel of NSCLC cell lines in vitro. Mocetinostat target gene promoters were occupied by a class I HDAC and exhibited increased active histone marks after mocetinostat treatment. Mocetinostat synergized with interferon gamma (IFN-gamma) in regulating class II transactivator (CIITA), a master regulator of class II HLA gene expression. In a syngeneic tumor model, mocetinostat decreased intratumoral T-regulatory cells (Tregs) and potentially myeloid-derived suppressor cell (MDSC) populations and increased intratumoral CD8+ populations. In ex vivo assays, patient-derived, mocetinostat-treated Tregs also showed significant down regulation of FOXP3 and HELIOS. The combination of mocetinostat and a murine PD-L1 antibody antagonist demonstrated increased anti-tumor activity compared to either therapy alone in two syngeneic tumor models. Together, these data provide evidence that mocetinostat modulates immune-related genes in tumor cells as well as immune cell types in the tumor microenvironment and enhances checkpoint inhibitor therapy.