Combining repetitive element-specific T cells with epigenetic therapy to treat ovarian cancer

重复元件特异性 T 细胞与表观遗传疗法相结合治疗卵巢癌

• 批准号: 10613918
• 负责人: Erin Elizabeth Grundy
• 金额: $ 4.22万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613918
• 关键词: Antigen Presentation Pathway; Antigen Targeting; Antigens; Bioinformatics; Biological Assay; Blood donor; Cancer Model; Cancer Patient; Cancer cell line; Cell Differentiation process; Cells; Coculture Techniques; Color; Competence; Critical Thinking; Data; Development; Elements; Endogenous Retroviruses; Epigenetic Process; Epitopes; Excision; Experimental Designs; Flow Cytometry; Genes; Genetic Materials; Genetic Transcription; Genomic Segment; Genomics; Goals; HLA Antigens; Histocompatibility Antigens Class I; Human; Immune; Immune response; Immune system; Immunologics; Immunophenotyping; Immunosuppression; Immunotherapy; In Vitro; Innate Immune Response; Interferon Type II; Interferons; Knowledge; Laboratories; Lytic; Malignant - descriptor; Malignant neoplasm of ovary; Mentors; Normal tissue morphology; Operative Surgical Procedures; Patients; Peptide Library; Peptides; Positioning Attribute; Postdoctoral Fellow; Predisposition; Process; Proteins; Protocols documentation; Publishing; RNA; Recurrent disease; Repetitive Sequence; Research; Role; Running; Sampling; Scientist; Solid Neoplasm; Source; Specificity; Surface; Survival Rate; T cell therapy; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Transcript; Tumor Antigens; Up-Regulation; Viral; Virus; Whole Blood; anti-tumor immune response; bioinformatics tool; cancer cell; career; cell killing; chemotherapy; clinically relevant; curative treatments; cytotoxicity; epigenetic therapy; experience; experimental study; immunodeficient mouse model; immunogenic; immunogenicity; in vivo; innovation; mimicry; mouse model; neoplastic cell; novel; novel therapeutic intervention; ovarian neoplasm; prediction algorithm; protein aminoacid sequence; response; skills; success; therapeutic target; transcriptome sequencing; treatment strategy; tumor; tumor immunology; tumor microenvironment; tumor-immune system interactions; viral RNA

The five year survival rate for ovarian cancer (OC) patients has remained at 47% for over two decades. OC is characterized by a highly suppressive tumor microenvironment and current research efforts focus on reversing this immune suppression. One way to activate the immune response against OC is using epigenetic therapeutics, which stimulate an interferon response in cancer cells by inducing the transcription of repetitive elements (REs)—genomic regions that resemble the genetic material of some viruses. As REs are normally silent in terminally differentiated cells, their upregulation in tumor cells suggests that these genomic elements can be used as inducible treatment targets. T cells specific for an RE-derived antigen, the non-functional envelope gene of endogenous retrovirus K (ERV-K-Env), can recognize their cognate antigen and kill OC cells while sparing healthy cells. Whether these T cells will be more lytic when combined with immunogenic epigenetic therapy is unknown. Aside from ERV-K-Env, other epigenetically upregulated REs serve as an unexplored pool of tumor-associated antigens that may be novel treatment targets. I hypothesize that combining epigenetic therapy with RE-specific T cells will have potent immunogenic and targeted anti-tumor efficacy in OC. In Aim 1, I will determine the effect of combination epigenetic therapy and ERK-K-Env-specific T cells in OC. Preliminary data suggest this candidate RE, ERV-K-Env, is a targetable tumor-associated antigen in OC. I hypothesize that combining epigenetic therapy with ex vivo expanded ERV-K-Env-specific T cells will result in targeted immunogenic OC cell killing. ERV-K-Env-specific T cells will be expanded ex vivo from whole blood donors and assessed in vitro for antigen specificity. I will co-culture the expanded T cells with epigenetically treated OC cells and assess T cell activation and cytotoxicity in vitro and in vivo. In Aim 2, I will identify and target additional tumor-associated RE peptides as novel OC tumor antigens. Preliminary data from my lab suggest that epigenetic treatment results in the upregulation of REs and their presentation on the surface of OC cells to the immune system. I hypothesize that diverse tumor-associated REs upregulated by epigenetic therapy can be therapeutically relevant T cell targets in OC. Bioinformatic tools will be used to identify which REs upregulated by epigenetic therapy have the potential to be T cell antigens. I will validate the immunogenicity of these antigens by expanding RE-specific T cells from healthy donors and assess the clinical relevance of the experimentally validated REs as treatment targets using OC patient T cells. Completion of the proposed project will provide new knowledge on the combination of epigenetic therapy with RE-specific T cells as a novel immunogenic and potentially curative treatment strategy for OC. Collectively, these innovative interdisciplinary experiments will shed light on the understudied role of REs as therapeutic targets while further elucidating the mechanisms involved in activating an anti-tumor immune response that may be applicable to other solid tumors.

二十多年来，卵巢癌（OC）患者的五年生存率一直保持在47%。 OC的特点是高度抑制肿瘤微环境，目前的研究工作集中在 逆转这种免疫抑制激活免疫反应对抗OC的一种方法是利用表观遗传学 治疗剂，其通过诱导癌细胞中的重复转录来刺激干扰素应答， 元件（RE）-类似于某些病毒遗传物质的基因组区域。因为RE通常 在终末分化细胞中沉默，它们在肿瘤细胞中的上调表明这些基因组元件 可作为诱导治疗靶点。对RE衍生抗原特异性的T细胞，非功能性T细胞， 内源性逆转录病毒K的包膜基因（ERV-K-Env）可以识别其同源抗原并杀死OC细胞 而不伤害健康细胞当与免疫原性表观遗传学结合时，这些T细胞是否会更具溶解性 治疗是未知的。除ERV-K-Env外，其他表观遗传上调的RE作为未探索的库 肿瘤相关抗原可能是新的治疗靶点。我假设结合表观遗传学 用RE特异性T细胞的治疗将在OC中具有有效的免疫原性和靶向抗肿瘤功效。 在目标1中，我将确定表观遗传疗法和ERK-K-Env特异性T细胞的组合在 OC.初步数据表明，这种候选RE ERV-K-Env是OC中的靶向肿瘤相关抗原。我 假设将表观遗传疗法与离体扩增的ERV-K-Env特异性T细胞组合将 导致靶向免疫原性OC细胞杀伤。ERV-K-Env特异性T细胞将从ERV-K-Env细胞中离体扩增。 全血供体并在体外评估抗原特异性。我将扩增的T细胞与 表观遗传学处理的OC细胞，并在体外和体内评估T细胞活化和细胞毒性。 在目标2中，我将鉴定和靶向其他肿瘤相关RE肽作为新的OC肿瘤抗原。 我实验室的初步数据表明，表观遗传治疗导致RE及其受体的上调。 在OC细胞表面上向免疫系统呈递。我假设不同的肿瘤相关的 通过表观遗传疗法上调的RE可以是OC中治疗相关的T细胞靶点。生物信息 将使用工具来鉴定哪些被表观遗传疗法上调的RE具有成为T细胞抗原的潜力。 我将通过扩增来自健康供体的RE特异性T细胞来验证这些抗原的免疫原性， 使用OC患者T细胞评估实验验证的RE作为治疗靶标的临床相关性。 完成拟议的项目将提供新的知识相结合的表观遗传疗法 RE特异性T细胞作为OC的一种新型免疫原性和潜在治愈性治疗策略。总的来说， 这些创新性的跨学科实验将揭示RE作为治疗剂的未充分研究的作用， 同时进一步阐明了参与激活抗肿瘤免疫应答的机制， 适用于其他实体瘤。