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Single-Cell Transcriptome & Effect of Immune Checkpoint Therapy on Kaposi Sarcoma

单细胞转录组

基本信息

批准号：
10417051
负责人：
Lee Ratner
金额：
$ 23.63万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-03 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10417051
关键词：
AIDS Malignancy Consortium Accounting Acquired Immunodeficiency Syndrome Adipocytes Admixture Adverse effects Africa South of the Sahara Angiogenesis Inhibitors Anthracycline Anti-HIV Therapy Apoptosis B-Lymphocytes Biological Assay Biopsy Blood Blood Vessels CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Compartmentation Cell Line Cells Characteristics Clinical Clinical Research Clinical Trials Complex Correlative Study Country Data Dendritic Cells Development Diagnosis Disease Disease remission Elderly man Endothelial Cells Endothelium Erythrocytes Fibroblasts Gene Expression Gene Expression Profiling Genes Genomics Goals Granzyme HIV HIV Seronegativity HIV-1 Immune Immune checkpoint inhibitor Immune response Immunologic Surveillance Immunomodulators Immunosuppression Immunotherapy In complete remission Individual Infection Infectious Agent Infiltration Inflammatory Inflammatory Infiltrate Kaposi Sarcoma Limited Stage Liposomes Local Therapy Lymphatic Endothelial Cells Lymphatic Endothelium Lymphoid Lymphoid Cell Lymphoma Lytic Malignant Neoplasms Mesenchymal Metabolic Metabolic Pathway Molecular Mononuclear Multicentric Angiofollicular Lymphoid Hyperplasia Natural Killer Cells Nivolumab Pathologic Pathway interactions Patient Selection Patients Pattern recognition receptor Phase Plasma Plasma Cells Primary carcinoma of the liver cells Progressive Disease Property Proteasome Inhibitor RNA Sequence Analysis Refractory Reporting Resolution SECTM1 gene Sampling Solid Neoplasm Stomach Carcinoma Stromal Cells Supporting Cell Syndrome Systemic Therapy T cell response T-Lymphocyte Transcript Transplant Recipients Viral Genes Virus Withdrawal angiogenesis antiretroviral therapy arm cancer cell cell type checkpoint therapy chemokine chemotherapy cost cytokine design follow-up gammaherpesvirus gene product immune reconstitution immunosuppressed inhibitor inhibitor therapy latent gene expression macrophage male neoplastic neoplastic cell novel population based predicting response predictive marker primary effusion lymphoma programmed cell death ligand 1 programmed cell death protein 1 response single-cell RNA sequencing taxane transcriptome transcriptome sequencing transcriptomics treatment response tumor tumor microenvironment vascular abnormality viral interferon regulatory factor

项目摘要

Abstract – Single-Cell Transcriptome & Effect of Immune Checkpoint Therapy on Kaposi Sarcoma Kaposi Sarcoma (KS) is a malignancy resulting from KS γ-herpresvirus (KSHV) infection occurring in immunosuppressed individuals, as well as a disease occurring primarily in males in subSaharan Africa and southern Mediterranean countries. The tumor is thought to arise from lymphatic endothelial cells, but it is pathologically complex with an admixture of vascular-like slits, spindle cells, and infiltrating inflammatory cells. KSHV is found in a subset of tumor cells with either lytic or latent gene expression profiles. Due to this complexity, there is very limited information about genomic and transcriptomic characteristics of this malignancy. The development of single cell (sc) transcriptomics (RNA-seq) provides a unique opportunity to identify key characteristics that underlie the development of KS. Treatment of KS involves local therapies, chemotherapy, angiogenesis or proteasome inhibitors, or immunotherapies, such as immunomodulatory drugs (IMiDs) or immune checkpoint inhibitors. Recent findings have suggested that KS responds to inhibitors of the programmed death-1(PD-1) pathway in approximately 20- 30% of individuals, but may rarely cause severe inflammatory KSHV-associated disorders. The current project will take advantage of an expansion arm of our current trial of nivolumab in HIV-associated KS. We will select samples before and after 2 months of nivolumab treatment from the 5 individuals with the best response and 5 individuals with progressive disease or no response to treatment. One goal of the current project is to identify pre-treatment characteristics, using scRNA-seq, that predict response or progression of KS treatment with PD- 1 inhibitor, nivolumab. A second goal of this project is to determine what changes of cell composition and gene expression occur with nivolumab in tumor cells and the tumor microenvironment. The aims are as follows: Aim 1. Determine the effect of PD-1 checkpoint inhibitor therapy on lymphoid infiltration into KS tumors. We will use scRNA-seq to enumerate B, CD4+ and CD8+ lymphocytes, natural killer, dendritic, and plasma cells, macrophages, mesenchymal, endothelial, and other cells in samples before and after nivolumab treatment. Aim 2. Determine the effect of PD-1 checkpoint inhibitor therapy on cellular and viral gene expression. We will use scRNA-seq to quantify levels of expression of KSHV lytic and latent genes, as well as expression of cellular genes in angiogenesis, proliferation, apoptosis, and metabolic pathways.

摘要-单细胞转录组和免疫检查点疗法对卡波西肉瘤的影响卡波西肉瘤（KS）是一种由KS γ-疱疹病毒（KSHV）感染引起的恶性肿瘤，免疫抑制个体，以及主要发生在撒哈拉以南非洲男性中的疾病，地中海南部国家。肿瘤被认为是从淋巴管内皮细胞，但它是病理上复杂，混合有血管样裂缝、梭形细胞和浸润性炎性细胞。 KSHV存在于具有裂解或潜伏基因表达谱的肿瘤细胞亚群中。由于这种复杂性，关于这种恶性肿瘤的基因组和转录组学特征的信息非常有限。的单细胞（sc）转录组学（RNA-seq）的发展提供了一个独特的机会，这些特点是知识产权发展的基础。 KS的治疗包括局部治疗、化疗、血管生成或蛋白酶体抑制剂，或免疫疗法，如免疫调节药物（IMiD）或免疫检查点抑制剂。最近的调查结果已经表明KS对程序性死亡-1（PD-1）通路抑制剂的反应大约在20- 30分钟内。 30%的个体，但可能很少引起严重的炎症KSHV相关疾病。当前项目将利用我们目前在HIV相关KS中进行的nivolumab试验的扩展臂。我们将选择在纳武单抗治疗2个月之前和之后，来自具有最佳应答的5个个体和来自具有最佳应答的5个个体的5个样本。患有进行性疾病或对治疗无反应的个体。本项目的一个目标是确定使用scRNA-seq的治疗前特征，其预测KS治疗与PD的反应或进展- 1抑制剂，纳武单抗。该项目的第二个目标是确定细胞组成和基因的变化 nivolumab在肿瘤细胞和肿瘤微环境中发生表达。其目标如下：目标1.确定PD-1检查点抑制剂治疗对KS肿瘤淋巴浸润的影响。我们将使用scRNA-seq计数B、CD 4+和CD 8+淋巴细胞、自然杀伤细胞、树突状细胞和浆细胞，图10示出了纳武单抗处理之前和之后样品中的巨噬细胞、间充质细胞、内皮细胞和其他细胞的细胞毒性。目标二。确定PD-1检查点抑制剂治疗对细胞和病毒基因表达的影响。我们将使用scRNA-seq来定量KSHV裂解和潜伏基因的表达水平，以及KSHV基因的表达水平。血管生成、增殖、凋亡和代谢途径中的细胞基因。