(PQ1) HIV-infected T-cell exosomes in lung cancer progression

(PQ1) HIV 感染的 T 细胞外泌体在肺癌进展中的作用

• 批准号: 10202519
• 负责人: Ge Jin
• 金额: $ 75.69万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10202519
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adjuvant; Age; Aging; Allografting; Automobile Driving; Benign; Blood; Blood Circulation; Body Fluids; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cancer Model; Cancer Patient; Cancer cell line; Cell Nucleus; Cell Proliferation; Cells; Cessation of life; Data; Development; Diagnosis; Distant; Endocytic Vesicle; Endosomes; Epidermal Growth Factor Receptor; Epithelial Cells; FVB Mouse; Foundations; General Population; Genetically Engineered Mouse; Growth; HIV; HIV Infections; HIV Seropositivity; HIV-1; Human; Immune; Immunologics; In Vitro; Individual; KRASG12D; Lead; Light; Liposomes; Longevity; Lung; MAPK3 gene; MEKs; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Mediating; Membrane Proteins; Methods; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Neoplasm Metastasis; Patients; Persons; Phosphorylation; Plasma; Population; Prevention; Production; Prognosis; Proteome; Proto-Oncogenes; Publishing; RNA; Ras/Raf; Relative Risks; Research; Response Elements; Risk; Risk Factors; Role; Signal Transduction; Site; Son of Sevenless Proteins; Specimen; T-Lymphocyte; TLR3 gene; Testing; Therapeutic Intervention; Transactivation; Transgenic Mice; Tumor Tissue; Tumor stage; Urethane; antiretroviral therapy; aptamer; cancer cell; cancer specimen resource; cell motility; chemical carcinogen; exosome; extracellular vesicles; in vivo; inhibitor/antagonist; intercellular communication; lung allograft; lung cancer cell; lung tumorigenesis; migration; mouse model; novel; novel strategies; patient derived xenograft model; reconstitution; response; success; transplant model; trend; tumor progression; tumorigenesis

Project Summary/Abstract Lung cancer (LCa) is the second most common malignancy in the US with about 222,500 new cases and 155,900 deaths each year. HIV-infected individuals and AIDS patients have increased relative risk of LCa by 250% after controlling for other potential risk factors. LCa in HIV+ people under antiretroviral therapy (ART) is diagnosed at younger ages than those in the general population. This trend in the ART era is implicitly attributed to prolonged life span and aging of the population. The success of new approaches to control lung tumorigenesis in the population is contingent to identify HIV-specific mechanisms that facilitate the tumor progression and metastasis. HIV-infected T cells release a variety of immunologically active exosomes, small vesicles of endocytic origin, to influence intercellular communication and material transfer at both local and distant sites, thus potentially contribute to enhanced risk for tumorigenesis. Our preliminary studies have found that exosomes secreted by HIV-infected T cells and purified from the blood of lung cancer patients of people living with HIV (PLWH) significantly stimulated lung cancer cell proliferation. HIV-associated exosomes induced MAP kinase ERK1/2 activation via interaction with epidermal growth factor receptor (EGFR) and the toll like receptor 3 (TLR3). Mechanistically, the HIV trans-activation response (TAR) element RNA, which exists in excess of other HIV RNAs in exosome from HIV-infected T cells, is responsible for enhanced cancer cell proliferation and proto-oncogene expression. We have established a bone marrow transplant (BMT) mouse model in which lethally-irradiated FVB mice were grafted with syngeneic bone marrow cells of Tg26 HIV- transgenic mice. Growth and metastasis of allografts LCa cells were significantly enhanced in grafted mice containing HIV+ bone marrow cells compared with that in non-grafted control mice. However, reconstitution of circulating immune cells and bone marrow remained the same between two groups of mice, suggesting that TAR RNA-bearing exosomes from reconstituted HIV+ immune cells may promote LCa progression in the BMT model. Taken together, these data lead us to hypothesize that TAR RNA-bearing exosomes from HIV-infected immune cells promote lung cancer growth and progression and that controlling release of the exosomes or directly targeting the TAR RNA may serve as an adjuvant for prevention and treatment of lung cancer in HIV- infected individuals. To test this hypothesis, we will first delineate the mechanism by which HIV-1-infected T- cell exosomes stimulate LCa growth and progression in vivo using the BMT model. The potentials for therapeutic intervention of LCa promotion by HIV will be examined through inhibition of exosome production and neutralization of TAR RNA. Finally, we will comprehensively examine the HIV-positive exosomal membrane proteins for interaction with EGFR and HIV-specific cargo components in the circulation using our novel EV-omics approach. Completion of the proposed studies will shed light on the mechanisms underlying HIV-mediated promotion of LCa and lay a foundation for therapeutic intervention of non-AIDS-defining cancers.

项目总结/摘要 肺癌（LCa）是美国第二常见的恶性肿瘤，约有222，500例新发病例， 每年有155，900人死亡。HIV感染者和AIDS患者LCa的相对风险增加， 在控制其他潜在风险因素后，250%。接受抗逆转录病毒治疗（ART）的艾滋病毒阳性者的LCa是 在比一般人群更年轻的年龄诊断。ART时代的这一趋势， 这是由于寿命延长和人口老龄化。控制肺部疾病新方法的成功 人群中的肿瘤发生取决于确定HIV特异性机制， 进展和转移。HIV感染的T细胞释放出多种免疫活性外泌体， 胞吞起源的囊泡，以影响局部和局部的细胞间通讯和物质转移， 远距离的位点，因此可能有助于增加肿瘤发生的风险。我们的初步研究发现 由HIV感染的T细胞分泌并从肺癌患者的血液中纯化的外泌体 艾滋病病毒携带者（PLWH）显著刺激肺癌细胞增殖。HIV相关外泌体诱导 MAP激酶ERK 1/2通过与表皮生长因子受体（EGFR）等相互作用激活 受体3（TLR 3）。从机制上讲，HIV反式激活反应（TAR）元件RNA，存在于 来自HIV感染的T细胞的外泌体中过量的其他HIV RNA，负责增强癌细胞 增殖和原癌基因表达。我们建立了一个骨髓移植（BMT）小鼠 将致死剂量照射的FVB小鼠移植入Tg 26 HIV-的同基因骨髓细胞的模型 转基因小鼠LCa细胞在移植小鼠体内的生长和转移能力明显增强 含有HIV+骨髓细胞的小鼠与未移植的对照小鼠相比。然而，重建 循环免疫细胞和骨髓在两组小鼠之间保持相同，这表明， 来自重建的HIV+免疫细胞的携带TAR RNA的外泌体可能促进BMT中的LCa进展 模型总之，这些数据使我们假设来自HIV感染者的携带TAR RNA的外泌体， 免疫细胞促进肺癌生长和进展以及外泌体或 直接靶向TAR RNA可作为预防和治疗HIV-1感染者肺癌的佐剂。 感染的人。为了验证这一假设，我们将首先描述HIV-1感染T细胞的机制， 细胞外泌体使用BMT模型在体内刺激LCa生长和进展。的潜能 将通过抑制外泌体的产生来检查HIV促进LCa的治疗性干预 和TAR RNA的中和。最后，我们将全面检查HIV阳性外泌体， 使用我们的方法，研究了在循环中与EGFR和HIV特异性货物组分相互作用的膜蛋白。 新的EV组学方法。完成拟议的研究将有助于了解其背后的机制 HIV介导的LCa的促进作用，为非AIDS定义的癌症的治疗性干预奠定基础。