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(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.

项目总结/文摘