(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: 10436288
• 负责人: Ge Jin
• 金额: $ 77.41万
• 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/10436288
• 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; 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.

项目摘要/摘要 肺癌(LCA)是美国第二常见的恶性肿瘤，约有22.25万新病例和 每年有155,900人死亡。HIV感染者和艾滋病患者通过以下方式增加了LCA的相对风险 在控制了其他潜在风险因素后为250%。接受抗逆转录病毒治疗(ART)的HIV+患者的LCA是 确诊的年龄比一般人群要小。艺术时代的这种趋势隐含着 这是由于人口寿命延长和老龄化所致。控制肺的新方法的成功 人群中的肿瘤发生与确定促进肿瘤发生的HIV特异性机制有关 进展和转移。HIV感染的T细胞释放各种具有免疫活性的外体，小的 胞内起源的小泡，影响局部和局部的细胞间通讯和物质转移 因此，较远的部位可能会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血液中纯化的外切体 艾滋病毒携带者(PLWH)显著刺激肺癌细胞增殖。人类免疫缺陷病毒相关外切体诱导 MAP激酶ERK1/2与表皮生长因子受体(EGFR)和Toll样蛋白的相互作用 受体3(TLR3)。从机制上讲，HIV反式激活反应(TAR)元件RNA，存在于 HIV感染的T细胞的外体中过量的其他HIV RNA是导致癌细胞增强的原因 增殖和原癌基因表达。我们建立了一只骨髓移植(BMT)小鼠 致死剂量照射的FVB小鼠移植TG26 HIV-26同基因骨髓细胞的模型 转基因小鼠。同种异体小鼠移植LCA细胞的生长和转移能力显著增强 将含有HIV+骨髓细胞的小鼠与未移植的对照组小鼠进行比较。然而，重组 循环免疫细胞和骨髓在两组小鼠之间保持相同，这表明 重组HIV+免疫细胞中携带TAR RNA的外切体可能促进骨髓移植LCA进展 模特。综上所述，这些数据让我们推测，携带TAR RNA的外切体来自艾滋病毒感染者 免疫细胞促进肺癌的生长和进展，控制外切体的释放或 直接靶向TAR RNA可能作为预防和治疗HIV肺癌的佐剂- 被感染的人。为了验证这一假说，我们将首先描述HIV-1感染的T细胞- 细胞外切体通过骨髓移植模型在体内刺激LCA的生长和进展。潜在的 HIV促进LCA的治疗干预将通过抑制外切体产生来检验 和TAR RNA的中和。最后，我们将全面检查HIV阳性的外切体 使用OURS技术用于与循环中的EGFR和HIV特异性货物成分相互作用的膜蛋白 新的电动汽车组学方法。拟议研究的完成将有助于阐明 HIV介导的LCA的促进，并为非AIDS定义的癌症的治疗干预奠定了基础。