Pathogenesis of the cART unresponsive Kaposi’s sarcoma tumor niche

cART 无反应卡波西肉瘤肿瘤微环境的发病机制

• 批准号: 9756172
• 负责人: MICHAEL Shannon MCGRATH
• 金额: $ 57.87万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756172
• 关键词: Acquired Immunodeficiency Syndrome; Address; Africa South of the Sahara; Anti-Retroviral Agents; B-Cell Activation; B-Lymphocytes; Biocompatible Materials; Bioinformatics; Biological Assay; Biopsy; CD3 Antigens; CD8B1 gene; Case Study; Categories; Cell Count; Cell Line; Cells; Clinical; Clinical Trials; Complex; Complex Mixtures; Cytokine Signaling; DNA; Data; Data Set; Detection; Development; Diagnosis; Disease; Disease remission; Elements; Ensure; Environment; Evaluation; Future; Gene Expression; Gene Expression Profiling; Genes; Genotype; Growth Factor; HIV; Histologic; Human; Human Herpesvirus 8; Imaging technology; Immune; Immune system; Immunohistochemistry; Immunologic Factors; Immunologics; In Vitro; Individual; Infection; Infiltration; Inflammatory; Kaposi Sarcoma; Lytic Virus; MS4A1 gene; Machine Learning; Malignant Neoplasms; Nature; Outcome; Participant; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Phylogenetic Analysis; Physical environment; Plasma; Play; Population; Population Sizes; Process; RNA; Rest; Risk; Role; Serous; Statistical Data Interpretation; Structure; T-Lymphocyte; Technology; Testing; Tissue Banks; Tissue Microarray; Tissues; Tropism; Tumor Tissue; United States; Up-Regulation; Viral; Viral Genes; Viral Load result; Viral Proteins; Virus; Virus Diseases; antiretroviral therapy; base; chemotherapy; clinically relevant; cohort; combinatorial; cytokine; deep sequencing; experience; experimental study; immunoregulation; in vivo; innovation; macrophage; mortality; novel; recruit; single molecule real time sequencing; therapy resistant; transcriptome; transcriptome sequencing; tumor; tumor microenvironment; tumor progression

Abstract Kaposi's Sarcoma (KS) is the most common AIDS-defining cancer. Combined anti-retroviral therapy (cART) has greatly reduced KS-associated mortality among AIDS patients; however, a serous clinical problem exists in that up to 50% of HIV+KS+ patients in the United States and 61% in Sub-Saharan Africa never achieve complete remission even with chemotherapy and a reduction in HIV viral loads. No definitive study has identified if there are tumor-associated features or mechanisms are associated with cART-progressive KS (progressors) vs. the responder (responders) phenotype. Our study utilizes a robust pre-cART KS tissue collection (n = 224) from the ACSR that originated from the Antiretrovirals for Kaposi's Sarcoma (ARKS) clinical trial. 36% of ARKS participants experienced continued progression of KS despite a reduction in viral loads and restored T-cell counts, in contrast to the rest of the cohort who experienced a reduction or elimination of tumors by the 1-year trial endpoint. This application poses several hypotheses concerning the progressor phenotype: 1) prior to the initiation of cART, an increase in HIV and/or KSHV-infected immune cells enhances a stimulatory immunological profile in the progressor phenotype, 2) there are significant differences in the upregulation of KSHV lytic and immunomodulation genes, which stimulate increased immune cell recruitment into the pre-cART tumor microenvironment and promote tumor progression through cytokine-signaling inflammatory processes enhanced in part by the cART-revitalized immune system, 3) the highly inflammatory nature of KS tumors, comprising a complex mixture of immune cells with which to interact, selects for unique and/or elusive HIV genotypes, distinct from plasma HIV, that promote stimulatory processes to continue in the progressor phenotype. Our Specific Aims address these hypotheses using a combination of advanced immunohistochemistry, virus specific cellular localization (DNA and RNAscope), high-throughput gene expression analysis (RNAseq), and a novel deep sequencing approach applied to HIV. Innovations include the unprecedented amount pre-cART KS tumor material available for the study, advanced imagining technologies, in vivo KS tumors gene expression studies, the use of the newer PacBio SMRT sequencing approach applied to HIV, and machine-learning approaches that can define non-linear associations in complex data sets. This project will define the largest well-characterized set of combinatorial features related to cART-associated KS outcomes derived directly from KS-associated biomaterial. Identifying clinically relevant immune factors in the tumor niche pre-cART will pave the way for the development of future mechanistic studies on the functions of both viral and cellular genes that are involved in cART resistant tumor progression.

抽象的 卡波西肉瘤 (KS) 是最常见的艾滋病定义癌症。联合抗逆转录病毒疗法（cART） 大大降低了艾滋病患者中与 KS 相关的死亡率；然而，存在严重的临床问题 在美国，高达 50% 的 HIV+KS+ 患者和撒哈拉以南非洲地区的 61% 患者从未实现完全康复 即使通过化疗和减少艾滋病病毒载量也能缓解。尚无明确的研究表明是否存在 肿瘤相关特征或机制是否与 cART 进展型 KS（进展者）相关 反应者（responders）表型。我们的研究利用了来自 cART KS 之前的强大组织收集（n = 224） ACSR源于抗逆转录病毒治疗卡波西肉瘤（ARKS）临床试验。方舟 36% 尽管病毒载量减少且 T 细胞恢复，但参与者仍经历了 KS 的持续进展 与其他队列中在一年内肿瘤减少或消除的人相比 试验终点。该申请提出了关于进展表型的几个假设：1) 在进展之前 cART 的启动，HIV 和/或 KSHV 感染的免疫细胞的增加增强了刺激性免疫学 进展表型的概况，2) KSHV 裂解和上调存在显着差异 免疫调节基因，刺激免疫细胞招募到 cART 前肿瘤中 微环境并通过增强细胞因子信号炎症过程促进肿瘤进展 部分是由于 cART 恢复活力的免疫系统，3) KS 肿瘤的高度炎症性质，包括 免疫细胞的复杂混合物与之相互作用，选择独特和/或难以捉摸的 HIV 基因型，独特的 来自血浆 HIV，促进刺激过程在进展者表型中继续。我们的具体 目的是结合先进的免疫组织化学、病毒特异性细胞分析来解决这些假设。 定位（DNA 和 RNAscope）、高通量基因表达分析（RNAseq）和新型深度分析 测序方法应用于艾滋病毒。创新包括前所未有的 cART 前 KS 肿瘤数量 可用于研究的材料、先进的成像技术、体内 KS 肿瘤基因表达研究、 使用适用于 HIV 的新型 PacBio SMRT 测序方法以及机器学习方法 可以定义复杂数据集中的非线性关联。该项目将定义最大的、特征鲜明的 与直接源自 KS 相关的 cART 相关 KS 结果相关的一组组合特征 生物材料。在 cART 之前识别肿瘤生态位中临床相关的免疫因子将为 对参与病毒和细胞基因功能的未来机制研究的发展 cART 耐药肿瘤进展。