Dissecting the Kaposi Sarcoma Tumor Microenvironment at the Single Cell Level

在单细胞水平剖析卡波西肉瘤肿瘤微环境

• 批准号: 10400022
• 负责人: Warren Phipps
• 金额: $ 63.48万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-09 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400022
• 关键词: AIDS related cancer; Adult; Africa South of the Sahara; Antigenic Specificity; Antigens; Automobile Driving; B-Lymphocytes; Bar Codes; Biopsy; Blood specimen; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Etiology; Cell physiology; Cells; Cessation of life; Clinical; Clone Cells; Complementary DNA; Complex; DNA; Data; Development; Disease; Ecosystem; Enrollment; Foundations; Frequencies; Gene Expression Profile; Gene Expression Profiling; Genes; Goals; HIV; HIV Infections; Histocompatibility Antigens Class I; Histologic; Human Herpesvirus 8; Immune; Immune response; Immune system; Immunology; Immunotherapy; Individual; Inflammation; Inflammatory Infiltrate; Institutes; Kaposi Sarcoma; Lead; Lentivirus; Malignant - descriptor; Malignant Neoplasms; Mediating; Molecular Profiling; Morbidity - disease rate; Open Reading Frames; Outcome; Pathogenesis; Peptides; Persons; Physiologic pulse; Plasmids; Play; Population Heterogeneity; Property; Prospective cohort study; Protocols documentation; Recombinants; Regulatory T-Lymphocyte; Risk; Role; Spindle Cell Neoplasm; Spindle Cell Sarcomas; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Testing; Tumor Biology; Tumor-Infiltrating Lymphocytes; Uganda; angiogenesis; antigen-specific T cells; antiretroviral therapy; base; cell type; cellular transduction; chronic infection; effector T cell; exhaustion; fighting; immune reconstitution; in vivo; insight; macrophage; mortality; neoplastic cell; neovasculature; new therapeutic target; novel therapeutic intervention; novel therapeutics; response; single-cell RNA sequencing; transcriptome sequencing; treatment response; tumor; tumor microenvironment; tumorigenesis; virology

PROJECT SUMMARY / ABSTRACT Kaposi sarcoma (KS) is among the most common of HIV-associated malignancies worldwide, and a leading cause of cancer morbidity and mortality in sub-Saharan Africa (SSA). Although KS can occur in HIV-uninfected individuals, particularly in SSA – termed “endemic” KS – HIV infection increases the risk of KS several thousand- fold. KS is a unique tumor whose pathogenesis involves chronic infection with HHV-8, disordered angiogenesis, and inflammation. Increasing evidence points to the importance of the interaction of these various components of the tumor microenviroment (TME) in driving tumorigenesis and response to treatment in a range of malignancies. However, our understanding of the composition and function of the KS TME is limited. Detailed study of the KS TME in vivo will elucidate mechanisms of KS pathogenesis, including the unique role of HIV infection, could elucidate fundamental aspects of tumor biology and help identify new therapeutic approaches. Since 2011 our team has been conducting a comprehensive prospective cohort study (“HIPPOS”) of KS in HIV+ and HIV- adults initiating treatment at the Uganda Cancer Institute in Kampala, Uganda. Subjects enrolled on this study provide blood samples and serial tumor biopsies and are followed for up to 1 year to rigorously define treatment response and clinical outcomes. Our results to date, based on study of over 160 KS subjects, suggest possible differences in the clinical outcome of HIV+ and HIV- KS subjects in Uganda, and have provided provocative preliminary data on the virology and immunology of KS in Uganda. Our team has recently developed and implemented a protocol for the isolation of viable single cells from KS tumors – including both tumor cells, tumor-infiltrating lymphocytes (TIL), and macrophages – that offers the unique opportunity to extend our studies of the role of HIV in the development and progression of KS to the single-cell level. In this application we propose to define the role of HIV in the KS tumor niche by performing comprehensive molecular profiling of isolated single tumor cells, TIL, and macrophages from serially acquired KS tumors from 20 HIV+ and 20 HIV- adults. The specific aims are: 1) To compare the transcriptional profile of KS tumor cells from HIV+ and HIV- subjects. 2) To perform serial transcriptional profiling of immune cells in KS tumors from HIV+ and HIV- adults, and to determine if changes in their transcriptional profiles are correlated with suppression of HIV and with treatment response. 3) To define the antigenic specificity of candidate CD8+ “public” HHV-8-specific infiltrating T cells in KS tumors that are associated with superior treatment response. The results of these studies will provide unprecedented insights into the role of HIV in the pathogenesis of KS and its response to treatment and could lay a foundation for antigen-specific immunotherapy of KS.

项目总结/摘要 卡波西肉瘤（KS）是世界范围内最常见的HIV相关恶性肿瘤之一，并且是主要的恶性肿瘤之一。 撒哈拉以南非洲（SSA）癌症发病率和死亡率的原因。虽然KS可以发生在未感染艾滋病毒的 个体，特别是在SSA中-称为“地方性”KS - HIV感染增加KS数千的风险- 折KS是一种独特的肿瘤，其发病机制涉及HHV-8的慢性感染，血管生成紊乱， 和炎症。越来越多的证据表明这些不同组成部分相互作用的重要性 肿瘤微环境（TME）在驱动肿瘤发生和对治疗的反应中的作用， 恶性肿瘤。然而，我们对KS TME的组成和功能的了解有限。详细 对KS TME的体内研究将阐明KS发病机制，包括HIV的独特作用 感染，可以阐明肿瘤生物学的基本方面，并帮助确定新的治疗方法。 自2011年以来，我们的团队一直在进行一项全面的KS前瞻性队列研究（“HIPPOS”）， 在乌干达坎帕拉的乌干达癌症研究所开始治疗的艾滋病毒阳性和艾滋病毒阴性成人。入组受试者 在这项研究中提供血液样本和一系列肿瘤活检，并随访长达1年，以严格 定义治疗反应和临床结果。我们迄今为止的研究结果是基于对160多名KS受试者的研究， 提示乌干达HIV+和HIV- KS受试者的临床结局可能存在差异，并提供了 关于乌干达KS病毒学和免疫学的初步数据。我们的团队最近开发了 并实施了从KS肿瘤中分离活的单细胞的方案-包括两种肿瘤细胞， 肿瘤浸润淋巴细胞（TIL）和巨噬细胞-这为我们的研究提供了独特的机会， HIV在KS发展和进展到单细胞水平中的作用。在本申请中，我们提出 通过对分离的单克隆抗体进行全面的分子分析，确定HIV在KS肿瘤生态位中的作用。 肿瘤细胞、TIL和巨噬细胞，来自20名HIV+和20名HIV-成人的连续获得的KS肿瘤。的 具体目标是： 1)比较来自HIV+和HIV-受试者的KS肿瘤细胞的转录谱。 2)对HIV+和HIV-成人KS肿瘤中的免疫细胞进行系列转录谱分析， 确定其转录谱的变化是否与HIV抑制和治疗相关 反应 3)确定KS肿瘤中候选CD 8+“公共”HHV-8特异性浸润T细胞的抗原特异性 与上级治疗反应相关。 这些研究的结果将为艾滋病毒在KS发病机制中的作用提供前所未有的见解 为KS的抗原特异性免疫治疗奠定基础。