Role of persistent type I IFN signaling in immune suppression and tumorigenesis during chronic HIV infection

持续的 I 型 IFN 信号在慢性 HIV 感染期间免疫抑制和肿瘤发生中的作用

基本信息

批准号：
10615053
负责人：
SCOTT G KITCHEN
金额：
$ 31.2万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615053
关键词：
Acceleration Acquired Immunodeficiency Syndrome Affect Animal Model Antiviral Response Attenuated Automobile Driving BLT mice Cells Chronic Clinical Trials Colorectal Cancer Complex Cross-Priming Cytotoxic T-Lymphocytes Dendritic Cells Deterioration Development Disease Disease Progression Effector Cell Engraftment Environment Foundations Functional disorder Future Gene Expression Goals Growth Growth and Development function HIV HIV Infections Hematology Human Immune Immune System Diseases Immune checkpoint inhibitor Immunocompetence Immunologic Surveillance Immunologics Immunosuppression Immunotherapy Infection Inflammation Inflammatory Interferon Receptor Interferon Type I Interferons Lymphocyte Malignant Neoplasms Mediating Myeloid-derived suppressor cells PD-1 blockade Patients Play Primates Process Production Proliferating Public Health Regimen Reporting Resistance Risk Role SIV Signal Transduction Solid System T cell response T-Lymphocyte Testing Therapeutic Therapeutic Intervention Tumor Antigens Tumor Cell Line Tumor Immunity Up-Regulation Viral Viral Load result Virus Diseases Virus Replication anti-cancer antiretroviral therapy cancer therapy cell type comorbidity cytokine driving force exhaustion humanized mouse immune activation immune checkpoint blockade immunoregulation improved in vivo innovation latent HIV reservoir melanoma mouse model neoplastic cell new therapeutic target novel novel strategies prevent response therapeutic target tumor tumor growth tumor immunology tumor microenvironment tumor-immune system interactions tumorigenesis type I interferon receptor

项目摘要

Project Summary HIV is a disease of inflammation and chronic immune activation. Ultimately, this results in severe immune dysfunctions and occurrence of other comorbidities, including cancer. In HIV disease, the mechanisms underlying chronic inflammation and how they contribute to immune deterioration and increased risk in cancer diseases as well as whether the ability to therapeutically interfere with this process could restore immune competence remain unclear. Across multiple species, including mouse models of chronic virus infection, SIV infection in primates, and HIV infection in humans, mounting evidence implicates type I interferon (IFN-I) signaling as a central mechanism underlying the chronic inflammation that drives the development of suppressive immune environment that promote cancer growth. The goal of this proposal is to elucidate the relationship between chronic IFN-I signaling, inflammation, immune exhaustion, and the development of an immuno-suppressive tumor niche that favors tumor growth. To achieve this goal, we will utilize a humanized mouse model that 1) allows engraftment and growth of multiple tumor cell lines and 2) recapitulates IFN-I induced immune activation and exhaustion during chronic HIV infection in vivo. We will utilize novel strategies to promote or block IFN-I signaling in vivo and an innovative approach to specifically generate tumor specific T cells to: (1) define the precise contribution of IFN-I signaling during HIV infection to the development of immuno-suppressive tumor enviroment and exhaustion of anti-tumor T cell that favor cancer growth; and (2) investigate if blocking chronic IFN-I signaling during chronic HIV infection can improve anti-tumor immunity and efficacy of immune checkpoint inhibitor blockade. Once completed, we strongly feel that our studies will significantly advance the understanding of the fundamental mechanisms that result in immune dysfunction and increased risk of AIDS and non-AIDS-related cancer. This will also provide the foundation, rationale, and system for future studies to define and therapeutically target inflammation and immune activation for cancer treatment with HIV infection.

项目概要 HIV是一种炎症和慢性免疫激活疾病。最终，这会导致严重的免疫反应功能障碍和其他合并症的发生，包括癌症。在艾滋病毒疾病中，机制潜在的慢性炎症及其如何导致免疫恶化和癌症风险增加疾病以及治疗干扰这一过程的能力是否可以恢复免疫能力仍不清楚。跨多个物种，包括慢性病毒感染的小鼠模型，SIV 灵长类动物感染和人类 HIV 感染，越来越多的证据表明 I 型干扰素（IFN-I）有关信号传导是慢性炎症的核心机制，可驱动疾病的发展抑制性免疫环境促进癌症生长。该提案的目标是阐明慢性 IFN-I 信号转导、炎症、免疫耗竭和免疫缺陷发展之间的关系有利于肿瘤生长的免疫抑制肿瘤生态位。为了实现这一目标，我们将利用人源化小鼠模型，该模型 1) 允许植入和生长多种肿瘤细胞系，2) 概括了慢性 HIV 期间 IFN-I 诱导的免疫激活和耗竭体内感染。我们将利用新的策略来促进或阻断体内 IFN-I 信号传导，并采用创新的方法特异性生成肿瘤特异性 T 细胞的方法可以：(1) 定义 IFN-I 信号传导的精确贡献 HIV感染过程中免疫抑制肿瘤环境的发展和抗肿瘤药物的耗尽有利于癌症生长的T细胞； (2) 研究是否在慢性 HIV 感染期间阻断慢性 IFN-I 信号传导可以提高抗肿瘤免疫力和免疫检查点抑制剂阻断的功效。一旦完成，我们强烈认为我们的研究将显着增进对导致免疫功能障碍和艾滋病及非艾滋病相关风险增加的基本机制癌症。这也将为未来的研究提供基础、原理和系统，以定义和治疗针对艾滋病毒感染的癌症治疗的炎症和免疫激活。