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：
8881950
负责人：
Katherine B Chiappinelli
金额：
$ 4.26万
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 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8881950
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 Health 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 antitumor effect 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 response sensor standard of care success targeted treatment transcription factor transcriptome sequencing 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）：在她的一生中，大约有67名美国妇女将患上上皮卵巢癌（EOC）。晚期疾病占病例的70％，五年生存率低于25％。在目前的护理标准下，手术进行了化学疗法，在过去的三十年中，EOC女性的生存变化很小。显然需要新的EOC疗法。表观遗传剂正在作为EOC和其他实体瘤的新疗法探索。肺癌患者的临床成功表明，DNA甲基转移酶抑制剂5-氮杂丁胺（AZA）和组蛋白脱乙酰基酶抑制剂Entinostat的作用可能刺激免疫反应，并靶向免疫细胞来消除肿瘤。此外，AZA还具有FDA批准用于治疗急性髓样白血病。癌症的特征是在肿瘤抑制基因的启动子处，包括组蛋白的DNA甲基化和脱乙酰化的抑制性染色质。 AZA抑制DNA甲基化，Entinostat抑制组蛋白脱乙酰基酶，打开染色质并引起抑制基因的转录。在EOC中，免疫基因和免疫细胞浸润到肿瘤中的较高表达预测了更好的预后。我们来自用AZA处理的23个EOC细胞系中的初步数据显示了与免疫反应有关的基因的上调。这些AZA诱导的免疫基因（AIM基因），代表了先天和适应性免疫的途径，来自TCGA的簇EOC肿瘤，表明一组具有低瞄准剂表达的肿瘤。在这笔赠款中，我建议使用AZA刺激EOC细胞中的免疫反应。这种疗法可以单独用于一部分患者，但应该使一组较大的患者对随后的免疫治疗敏感。我假设AZA引起的目标消除将导致癌细胞死亡并募集宿主免疫细胞对肿瘤，并可以使卵巢癌细胞敏感到随后的免疫疗法。 AZA激活上皮细胞免疫反应的机制尚不清楚。 AZA脱甲基化可能会导致免疫主调节剂的重新表达。我观察到正常沉默的RNA（例如人类内源性逆转录病毒（ERV）和重复元素，AZA治疗后可能会激活免疫（病毒防御）反应。另外，AZA可以在肿瘤上诱导免疫检查点配体PD-L1的表达。因此，我建议将表观遗传免疫调节与抑制PD-1/PD-L1途径相结合可能导致对EOC肿瘤的协同抗肿瘤作用。目标1：我将确定AZA免疫反应的表型效应和机制。 AIM 2：我将确定内源性逆转录病毒和可转座元件RNA是否负责AZA免疫反应。 AIM 3：我将使用AZA治疗以刺激免疫反应，然后在免疫功能的卵巢癌小鼠模型中进行抗PD-1抗体，以阻止免疫逃避，并评估宿主免疫细胞激活和肿瘤细胞杀伤。因此，我将评估在最致命的人类恶性肿瘤之一中结合表观遗传学与治疗以打破免疫耐受性的功效。