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The use of epigenetic therapy to activate an immune response in ovarian cancer

使用表观遗传学疗法激活卵巢癌的免疫反应

基本信息

批准号：
8780824
负责人：
Katherine B Chiappinelli
金额：
$ 5.15万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8780824
关键词：
Accounting Acute Myelocytic Leukemia Antibodies Antigen Presentation Antigens Apoptosis Azacitidine CD8B1 gene Cancer cell line Cell Death Cells Chromatin Clinic Clinical Coculture Techniques Collaborations Combined Modality Therapy DNA DNA Methylation DNA Methyltransferase Inhibitor DNA Transposable Elements Data Detection Disease Dose Double-Stranded RNA Endogenous Retroviruses Epigenetic Process Epithelial Epithelial Cells Epithelial ovarian cancer Epithelium Family Genes Genetic Transcription Goals Grant HERVs Histone Deacetylase Inhibitor Histone Deacetylation Histones Human Immune Immune Cell Activation Immune Response Genes Immune Targeting Immune Tolerance Immune response Immune system Immunocompetent Immunotherapy Implant In Vitro Infiltration Interferon Activation Interferon Receptor Interferons Lead Ligands Lymphocyte Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Mammalian Oviducts Mus Natural Immunity Natural Killer Cells Operative Surgical Procedures Ovarian Ovarian Clear Cell Tumor Pathway interactions Patients Pharmaceutical Preparations RNA RNA Interference RNA Sequences Repetitive Sequence Repression Retrotransposon Role Short Interspersed Nucleotide Elements Signal Transduction Solid Neoplasm Staging Survival Rate T-Lymphocyte Testing The Cancer Genome Atlas Transcript Tumor Immunity Tumor Suppressor Genes Universities Untranslated RNA Up-Regulation Viral Woman Work adaptive immunity cancer cell cancer immunotherapy cancer testis antigen cancer therapy cell killing cell transformation chemotherapy cytokine defense response demethylation immune activation immunoregulation knock-down mouse model neoplastic cell novel outcome forecast ovarian neoplasm overexpression programs promoter public health relevance response sensor standard of care success transcription factor tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Approximately one out of 67 U.S. women will get epithelial ovarian cancer (EOC) in her lifetime. Late-stage disease accounts for 70% of cases, with a dismal five year survival rate of less than 25%. Under the current standard of care, surgery followed by chemotherapy, survival of women with EOC has changed very little over the past three decades. Novel therapies for EOC are clearly needed. Epigenetic agents are being explored as new therapies for EOC and other solid tumors. Clinical success in patients with lung cancer suggests that the actions of the DNA methyltransferase inhibitor 5-azacytidine (AZA) and the histone deacetylase inhibitor entinostat may stimulate the immune response and target immune cells to eradicate tumors. Furthermore AZA has FDA approval for treatment of acute myeloid leukemia. Cancers are characterized by repressive chromatin, including DNA methylation and deacetylation of histones, at promoters of tumor suppressor genes. AZA inhibits DNA methylation and entinostat inhibits histone deacetylases, opening up chromatin and causing transcription of repressed genes. In EOC, higher expression of immune genes and immune cell infiltration into tumors predict better prognosis. Our preliminary data from 23 EOC cell lines treated with AZA show an upregulation of genes involved in the immune response. These AZA-Induced iMmune genes (AIM genes), representing pathways of both innate and adaptive immunity, cluster EOC tumors from TCGA and indicate a group of tumors with low AIM expression. In this grant I propose to use AZA to stimulate an immune response in EOC cells. This therapy could work alone for a subset of patients but should sensitize a larger group of patients to subsequent immune therapy. I hypothesize that an AZA-induced de-repression of AIMs will lead to cancer cell death and recruitment of host immune cells to the tumor and can sensitize ovarian cancer cells to subsequent immunotherapy. The mechanism by which AZA activates an epithelial cell immune response is unknown. Demethylation by AZA could cause re-expression of immune master regulators. I observe transcription of normally silenced RNAs such as human endogenous retroviruses (ERVs) and repetitive elements upon AZA treatment, which may activate the immune (viral defense) response. Separately, AZA can induce expression of the immune checkpoint ligand PD-L1 on tumors. Thus, I propose that combining epigenetic immune modulation with inhibition of the PD-1/PD-L1 pathway may result in synergistic anti-tumor effects against EOC tumors. Aim 1: I will determine the phenotypic effects and mechanism of the AZA immune response. Aim 2: I will determine whether endogenous retrovirus and transposable element RNAs are responsible for the AZA immune response. Aim 3: I will treat with AZA to stimulate the immune response, then an anti-PD-1 antibody to block immune evasion, in immunocompetent mouse models of ovarian cancer and assess host immune cell activation and tumor cell killing. I will thus assess the efficacy of combining epigenetic with therapy to break immune tolerance in one of the deadliest human malignancies.

描述（由申请人提供）：大约每67名美国女性中就有1人会在其一生中患上上皮性卵巢癌（EOC）。晚期疾病占病例的70%，5年生存率不到25%。在目前的护理标准下，手术后化疗，在过去的三十年中，EOC妇女的生存率几乎没有变化。显然需要新的EOC治疗方法。表观遗传因子作为EOC和其他实体瘤的新疗法正在被探索。肺癌患者的临床成功表明，DNA甲基转移酶抑制剂5-氮杂胞苷（5-azacytidine， AZA）和组蛋白去乙酰化酶抑制剂恩替司他（entinostat）的作用可能刺激免疫反应，靶向免疫细胞根除肿瘤。此外，AZA已获得FDA批准用于治疗急性髓性白血病。癌症的特点是抑制染色质，包括DNA甲基化和组蛋白去乙酰化，在肿瘤抑制基因的启动子。AZA抑制DNA甲基化，而entinostat抑制组蛋白去乙酰化酶，打开染色质并导致被抑制基因的转录。在EOC中，较高的免疫基因表达和免疫细胞浸润预示着较好的预后。我们对23株经AZA处理的EOC细胞系的初步数据显示，参与免疫反应的基因上调。这些aza诱导的免疫基因（AIM基因），代表了先天免疫和适应性免疫的途径，聚集了来自TCGA的EOC肿瘤，并指示了一组低AIM表达的肿瘤。在这项拨款中，我建议使用AZA来刺激EOC细胞的免疫反应。这种疗法可以单独对一部分患者起作用，但应该使更多的患者对随后的免疫治疗敏感。我推测，aza诱导的AIMs去抑制将导致癌细胞死亡和宿主免疫细胞向肿瘤募集，并可使卵巢癌细胞对随后的免疫治疗敏感。AZA激活上皮细胞免疫应答的机制尚不清楚。AZA去甲基化可引起免疫主调控因子的重新表达。我观察到正常沉默的rna，如人内源性逆转录病毒（erv）和重复元件在AZA治疗后的转录，这可能激活免疫（病毒防御）反应。另外，AZA可以诱导肿瘤上免疫检查点配体PD-L1的表达。因此，我提出将表观遗传免疫调节与抑制PD-1/PD-L1途径相结合可能会产生对EOC肿瘤的协同抗肿瘤作用。目的1：确定AZA免疫应答的表型效应和机制。目的2：我将确定内源性逆转录病毒和转座因子rna是否负责AZA免疫反应。目的3：我将在免疫功能正常的卵巢癌小鼠模型中使用AZA来刺激免疫反应，然后使用抗pd -1抗体来阻断免疫逃避，并评估宿主免疫细胞激活和肿瘤细胞杀伤。因此，我将评估将表观遗传学与治疗相结合的效果，以打破人类最致命的恶性肿瘤之一的免疫耐受。