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: 10020368
• 负责人: MICHAEL Shannon MCGRATH
• 金额: $ 56.7万
• 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/10020368
• 关键词: Acquired Immunodeficiency Syndrome; Address; Africa South of the Sahara; Anti-Retroviral Agents; B-Cell Activation; B-Lymphocytes; Bar Codes; 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; Tumor-infiltrating immune cells; United States; Up-Regulation; Viral; Viral Genes; Viral Load result; Viral Proteins; Virus; Virus Diseases; antiretroviral therapy; base; chemotherapy; clinically relevant; cohort; combinatorial; complex data; 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 Kaposi的肉瘤（KS）是定义癌症的最常见的。联合抗逆转录病毒疗法（CART）具有 艾滋病患者的KS相关死亡率大大降低了；但是，存在浆液临床问题 美国多达50％的HIV+ KS+患者和撒哈拉以南非洲的61％从未完成 即使进行化学疗法和HIV病毒负荷减少，缓解也是如此。没有确定的研究是否确定 与肿瘤相关的特征或机制与Cart-rogressivers KS（进度者）与 响应者（响应者）表型。我们的研究利用了从 ACSR起源于卡波西肉瘤（ARKS）临床试验的抗逆转录病毒。 36％的方舟 尽管病毒载荷减少并恢复了T细胞，参与者仍在继续发展KS 与其余的队列相比 试验端点。该应用程序提出了有关进度者表型的几个假设：1） 启动购物车，HIV和/或KSHV感染的免疫细胞的增加会增强刺激性免疫学 进度者表型中的特征，2）KSHV裂解和 免疫调节基因，刺激免疫细胞募集增加到前肿瘤中 微环境并通过细胞因子信号炎症过程促进肿瘤进展 部分由货车复活的免疫系统，3）KS肿瘤的高度炎症性质，包括A 免疫细胞相互作用的复杂混合物，选择独特和/或难以捉摸的HIV基因型，不同 从血浆艾滋病毒中，促进刺激过程以继续在进度者表型中。我们的具体 目的是通过晚期免疫组织化学，病毒特异性细胞的结合来解决这些假设 定位（DNA和RNASCOPE），高通量基因表达分析（RNASEQ）和新的深 应用于艾滋病毒的测序方法。创新包括前所未有的前KS肿瘤 可用于研究的材料，先进的想象技术，体内KS肿瘤基因表达研究， 使用新的PACBIO SMRT测序方法应用于HIV，以及机器学习方法 可以在复杂的数据集中定义非线性关联。该项目将定义最大的特色 与CART相关的KS结果有关的组合特征集直接从KS相关的 生物材料。识别肿瘤生态科中临床相关的免疫因素将为车铺平道路 开发有关病毒和细胞基因功能的未来机械研究 抗车肿瘤进展。