(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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要肺癌 (LCa) 是美国第二大常见恶性肿瘤，新增病例约 222,500 例每年有 155,900 人死亡。 HIV 感染者和 AIDS 患者发生 LCa 的相对风险增加控制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 是与一般人群相比，诊断年龄更小。 ART时代的这种趋势隐含着归因于寿命延长和人口老龄化。控制肺部新方法的成功人群中肿瘤的发生取决于确定促进肿瘤发生的 HIV 特异性机制进展和转移。 HIV感染的T细胞释放多种具有免疫活性的外泌体，小内吞起源的囊泡，影响局部和局部的细胞间通讯和物质转移远距离位点，因此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 细胞分泌的外泌体，并从肺癌患者的血液中纯化出来 HIV感染者（PLWH）显着刺激肺癌细胞增殖。 HIV相关外泌体诱导 MAP 激酶 ERK1/2 通过与表皮生长因子受体 (EGFR) 等相互作用而激活受体 3 (TLR3)。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 是增强癌细胞的原因增殖和原癌基因表达。我们建立了骨髓移植（BMT）小鼠模型中，经致死辐射的 FVB 小鼠被移植了 Tg26 HIV-的同基因骨髓细胞转基因小鼠。移植小鼠体内同种异体LCa细胞的生长和转移显着增强与未移植的对照小鼠相比，含有 HIV+ 骨髓细胞的小鼠。然而，重建两组小鼠之间的循环免疫细胞和骨髓保持相同，这表明来自重组 HIV+ 免疫细胞的 TAR RNA 外泌体可能促进 BMT 中的 LCa 进展模型。综上所述，这些数据使我们推测，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，并控制外泌体或直接靶向 TAR RNA 可能作为 HIV 患者肺癌预防和治疗的佐剂感染者。为了检验这一假设，我们将首先描述 HIV-1 感染的 T 细胞的机制。使用 BMT 模型，细胞外泌体在体内刺激 LCa 生长和进展。的潜力将通过抑制外泌体产生来检查 HIV 对 LCa 促进的治疗干预和 TAR RNA 的中和。最后，我们将全面检查HIV阳性的外泌体使用我们的膜蛋白与循环中的 EGFR 和 HIV 特异性货物成分相互作用新颖的 EV 组学方法。完成拟议的研究将揭示其背后的机制 HIV 介导的 LCa 促进，为非艾滋病定义癌症的治疗干预奠定了基础。