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: 9759709
• 负责人: Warren Phipps
• 金额: $ 65.85万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH 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/9759709
• 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; Genetic Transcription; Goals; HIV; HIV Infections; Histocompatibility Antigens Class I; Histologic; Human Herpesvirus 8; Immune; Immune response; Immune system; Immunoglobulin Variable Region; Immunology; Immunotherapy; Individual; Inflammation; Inflammatory Infiltrate; Institutes; Kaposi Sarcoma; Lead; 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; Subfamily lentivirinae; 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; 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.

项目概要/摘要 卡波西肉瘤 (KS) 是全世界最常见的 HIV 相关恶性肿瘤之一，也是一种主要的癌症 撒哈拉以南非洲 (SSA) 癌症发病率和死亡率的原因。尽管 KS 也可能发生在未感染 HIV 的人身上 个体，特别是在 SSA 中——被称为“地方性”KS——HIV 感染会增加数千人罹患 KS 的风险—— 折叠。 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成分相互作用的重要性 肿瘤微环境（TME）在驱动肿瘤发生和对一系列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是有限的。详细的 KS TME 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，我们的团队一直在对 KS 进行全面的前瞻性队列研究（“HIPPOS”） HIV+ 和 HIV- 成年人在乌干达坎帕拉的乌干达癌症研究所开始接受治疗。注册科目 在这项研究中，提供血液样本和连续肿瘤活检，并进行长达一年的严格随访 定义治疗反应和临床结果。迄今为止，我们的结果基于对 160 多名 KS 受试者的研究， 表明乌干达 HIV+ 和 HIV-KS 受试者的临床结果可能存在差异，并提供了 关于乌干达 KS 病毒学和免疫学的具有争议性的初步数据。我们团队最近开发了 并实施了从 KS 肿瘤中分离活单细胞的方案 - 包括肿瘤细胞， 肿瘤浸润淋巴细胞 (TIL) 和巨噬细胞——这为扩展我们的研究提供了独特的机会 HIV 在 KS 发展和进展至单细胞水平中的作用。在此应用中，我们建议 通过对分离的单个病毒进行全面的分子分析来确定 HIV 在 KS 肿瘤生态位中的作用 来自 20 个 HIV+ 和 20 个 HIV- 成人连续获得的 KS 肿瘤的肿瘤细胞、TIL 和巨噬细胞。这 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) 对来自 HIV+ 和 HIV- 成人的 KS 肿瘤中的免疫细胞进行连续转录分析，并 确定其转录谱的变化是否与 HIV 抑制和治疗相关 回复。 3) 定义 KS 肿瘤中候选 CD8+“公共”HHV-8 特异性浸润 T 细胞的抗原特异性 与优异的治疗反应相关。 这些研究结果将为了解 HIV 在 KS 发病机制中的作用提供前所未有的见解 及其对治疗的反应，可为 KS 的抗原特异性免疫治疗奠定基础。