Targeting Endogenous Retrovirus Regulation for Augmenting Cancer Immunotherapy

针对内源性逆转录病毒调节增强癌症免疫治疗

• 批准号: 10620376
• 负责人: Meaghan K. McGeary
• 金额: $ 9.14万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620376
• 关键词: Address; Animal Model; Antigen Presentation; Antigen Targeting; Antigens; Breast; Breast Melanoma; CD8-Positive T-Lymphocytes; CRISPR screen; Cancer Patient; Cancer cell line; Cells; Clinical; Colorectal; Complex; Coupled; Data; Deposition; Elements; Endogenous Retroviruses; Epigenetic Process; Euthanasia; Gene Expression; Generations; Genetic; Genetic Transcription; Histone Deacetylase Inhibitor; Human; Human Genome; I-antigen; IRF3 gene; Immune Targeting; Immune response; Immune system; Immunotherapeutic agent; Immunotherapy; Infection; Interferon Activation; Interferon Type I; Interferons; Knock-out; Knowledge; Lead; Malignant Neoplasms; Methylation; Methyltransferase; Mus; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Phase; Postdoctoral Fellow; Pre-Clinical Model; Prognosis; Proteins; Regulation; Renal Cell Carcinoma; Repression; Research; Resistance; Retroelements; Role; T-Lymphocyte; Testing; Therapeutic; Transcript; Tumor Antigens; Tumor Immunity; Up-Regulation; Viral; Viral Physiology; Work; Xenograft Model; anti-melanoma immunity; anti-tumor immune response; cancer immunotherapy; cancer type; cell killing; chimeric antigen receptor T cells; experience; immune activation; immune clearance; immunogenic; immunogenicity; immunomodulatory therapies; improved; improved outcome; in vivo; lung cancer cell; malignant breast neoplasm; melanoma; member; neoplastic cell; new therapeutic target; novel; response; targeted treatment; therapeutic development; tumor; tumor growth; tumor immunology; whole genome

PROJECT SUMMARY Immune-modulating therapies have been revolutionary treatments for several cancer types including melanoma, lung cancer, and renal cell carcinoma. However, most cancer patients do not respond to immunotherapies, and there remains a critical need to identify alternative approaches to treating these cancers. Endogenous retroviruses (ERVs) are genetic remnants of retroviral infection transmitted vertically through generations, whose transcription can result in type-I interferon activation, and/or presentation of ERV-associated antigens. Recent studies on ERVs in human cancer has shown that ERV expression can render cells immunogenic in a variety of cancer types including colorectal, breast cancer and melanoma. Therefore, characterization of how ERV expression is regulated in cancer will reveal opportunities to therapeutically de-repress ERVs and improve immunotherapy outcomes in low antigen tumors. In the F99-phase of this proposal, I will investigate the role of epigenetic factors regulating ERV expression and anti-tumor immunity in melanoma. Specifically, I will test melanoma tumors for ERV tetramer-positive CD8+ T cells, to determine the antigenicity of de-repressed melanoma ERVs. Furthermore, I will determine the mechanism by which type-I interferon response is induced in epigenetically-modified tumors, and determine the role of ERV MHC-I antigens through genetic knockouts of each component and evaluating tumor growth and immunogenicity. This work will establish the mechanism by which ERVs are regulated epigenetically, and establish a framework for investigating ERV regulation and its impact on the immune response to cancer. In the K00-phase of this proposal, I will harness my experience studying ERVs to investigate their utility in improving the immune response to antigen-low tumor types. Specifically, I will perform a CRISPR screen to identify druggable regulators of HERV expression in human cancer cell lines. I will then validate these candidate regulators by pharmacologically targeting them and testing the induction of type-I interferon and antigenic responses in these cells. Finally, I will evaluate whether ERV-specific CAR-T cells can react to ERV-induced cells in vivo. This proposed research will clarify the mechanisms by which ERVs are epigenetically regulated in cancer, and identify novel and actionable targets for re-expressing ERVs in difficult-to-treat tumor types. This will lead to improved immunotherapeutic strategies for treating cancers with poor patient outcomes.

项目摘要 免疫调节疗法一直是多种癌症类型的革命疗法，包括黑色素瘤， 肺癌和肾细胞癌。但是，大多数癌症患者对免疫疗法没有反应，并且 仍然需要确定治疗这些癌症的替代方法。内源性 逆转录病毒（ERV）是垂直传播的逆转录病毒感染的遗传残留物，其世代相传 转录可以导致I型干扰素激活和/或与ERV相关抗原的表现。最近的 关于人类癌症中ERV的研究表明，ERV表达可以使细胞在多种 癌症类型，包括结直肠癌，乳腺癌和黑色素瘤。因此，表征如何ERV 在癌症中调节表达将揭示治疗抑制ERV并改善的机会 低抗原肿瘤的免疫疗法结局。 在该提案的F99阶段中，我将研究调节ERV表达和的表观遗传因素的作用 黑色素瘤中的抗肿瘤免疫。具体而言，我将测试ERV四聚体阳性CD8+ T的黑色素瘤肿瘤 细胞，以确定脱皮的黑色素瘤ERV的抗原性。此外，我将确定 I型干扰素反应在表观遗传修饰的肿瘤中诱导的机制，并确定 ERV MHC-1抗原通过每个成分的遗传敲除并评估肿瘤生长和 免疫原性。这项工作将确定ERV受到表观遗传调节的机制，以及 建立一个研究ERV调节及其对癌症免疫反应的影响的框架。 在该提案的K00阶段，我将利用我的研究ERV的经验来调查其实用程序 改善对抗原 - 低肿瘤类型的免疫反应。具体来说，我将执行CRISPR屏幕 鉴定在人类癌细胞系中HERV表达的可药物调节剂。然后，我将验证这些候选人 通过药理学靶向调节器，并测试I型干扰素和抗原的诱导 这些细胞的反应。最后，我将评估ERV特异性CAR-T细胞是否可以对ERV诱导的反应 细胞体内。 这项拟议的研究将阐明ERV在癌症中表观遗传调节的机制，以及 确定在难以治疗的肿瘤类型中重新表达ERV的新颖靶标。这将导致 改善了治疗患者较差癌症的免疫治疗策略。