KSHV,HIV and the Kaposi's Sarcoma Tumor Niche

KSHV、HIV 和卡波西肉瘤肿瘤位

基本信息

批准号：
10424452
负责人：
John T West
金额：
$ 54.01万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10424452
关键词：
AIDS with Kaposi&apos s sarcoma Acquired Immunodeficiency Syndrome African American Antigens Antineoplastic Agents Autologous Automobile Driving B-Lymphocytes Biopsy CD14 gene CD4 Lymphocyte Count CD8-Positive T-Lymphocytes CD8B1 gene CXCL9 gene Cells Chemotactic Factors Collaborations Communities Cytomegalovirus Data Defect Development Diagnosis Disease Effector Cell Environment Etiology Evaluation Expression Profiling Failure HIV HIV-1 Herpesviridae Infections Human Herpesvirus 4 Human Herpesvirus 8 Iatrogenesis Immune Immune system Immunity Immunodominant Antigens Immunologics Immunophenotyping Immunosuppression Immunotherapeutic agent Incidence Individual Inflammatory Influenza Interleukin-10 Intervention Investigation Kaposi Sarcoma Knowledge Leukocytes Malignant Neoplasms Memory Molecular Nature Neoplasms Patients Pattern Peptides Peripheral Peripheral Blood Mononuclear Cell Phenotype Plasma Population Process Resected Role Skin Specificity Suspensions T cell differentiation T cell response T-Lymphocyte Teaching Hospitals Testing Therapeutic Tissues Tumor Tissue Tumor-Infiltrating Lymphocytes Universities Vaccines Viral Woman Zambia anergy antiretroviral therapy checkpoint inhibition co-infection comparative cytokine design exhaustion illness length immune reconstitution macrophage men neoplastic patient stratification programs response senescence transcriptome transcriptome sequencing tumor tumor microenvironment

项目摘要

PROJECT SUMMARY Epidemic Kaposi’s sarcoma (KS) is an HIV-1 associated tumor, and remains one of the highest incidence neoplasms in sub-Saharan African men and women despite effective antiretroviral therapy (ART) programs. The fundamental mechanism driving KS appears to be KSHV infection, but it is clear that KSHV infection alone is insufficient for KS development since most infected individuals do not develop KS. HIV-1 co-infection or therapeutic immune suppression induces, exacerbates, or accelerates KS disease. How HIV-1 co-infection synergizes with KSHV to form or maintain the tumor niche is largely unexplored in tissue. In many cancers, a clear understanding of the tumor microenvironment including the presence, antigen- specificity and functionality of tumor-infiltrating lymphocytes (TILs) is revolutionizing therapeutic approaches. Yet for KS we have a dearth of information about the nature of TILs and whether the tumor microenvironment is suppressing their anti-neoplastic function in an HIV-1 dependent manner. This project seeks to rectify this knowledge gap in a Case (HIV-1+/KS+) versus Control ((HIV-1+/KS-) design by comparatively investigating the phenotypes and the functionality of TILs in comparison to the same cells in the peripheral immune system and by comparing the tumor and peripheral immune cell expression patterns. Our hypothesis is that even in the face of a detectable KSHV-reactive peripheral T cell response and effective HIV-1 suppression, there are insufficient numbers of KSHV Ag-specifc tumor-infiltrating T lymphocytes (TILs) and these cells are non-responsive to antigen in KS tumors. Our approach is 1) to functionally compare the peripheral CD4 and CD8 T cell responses to KSHV and ubiquitous immunodominant antigens in KS with differential HIV-1 disease duration; 2) to isolate, and immunophenotypically and functionally characterize KS tumor infiltrating leukocytes; and 3) to compare the transcriptomes of TILs with autologous peripheral cells or those from KS asymptomatic controls. From these comparative investigations, we anticipate deriving a more robust understanding of the expression programs and immune responsiveness of adaptive immune cells in the KS tumor niche and more complete understanding of the role of HIV-1, immune suppression, anergy, exhaustion, and senescence in defining that niche. This understanding will direct interventional strategies including the design of immunotherapeutics and potentially vaccines against KS.

项目摘要流行病卡波西的肉瘤（KS）是HIV-1相关的肿瘤，仍然是最高的事件之一尽管有效的抗逆转录病毒疗法（ART）计划，撒哈拉以南非洲男性和女性的肿瘤。驱动KS的基本机制似乎是KSHV感染，但很明显，仅KSHV感染由于大多数受感染的人不发展KS，因此不足以开发KS。 HIV-1共感染或治疗性免疫抑制会诱导，加剧或加速KS病。 HIV-1如何共感染与KSHV协同形成或维持肿瘤生态位在组织中在很大程度上是意外的。在许多癌症中，对肿瘤微环境的清晰了解，包括存在，抗原 - 肿瘤浸润淋巴细胞（TILS）的特异性和功能是革命性的治疗方法。然而，对于KS，我们有有关TIL的性质以及肿瘤微环境的信息死亡正在以HIV-1依赖性方式抑制其抗肿瘤功能。这个项目旨在纠正这一点通过相对研究与外周免疫系统中的相同细胞相比，TIL的表型和功能并通过比较肿瘤和外周免疫球表达模式。我们的假设是，即使面对可检测到的KSHV反应性周围T细胞反应和有效 HIV-1抑制作用，数量不足，KSHV Ag特异性肿瘤浸润T淋巴细胞（TILS）这些细胞对KS肿瘤中的抗原无反应。我们的方法是1）在功能上比较对KSHV和无处不在的免疫主导抗原的外围CD4和CD8 T细胞反应KS 差异HIV-1疾病持续时间； 2）孤立和免疫异形和功能表征KS 肿瘤浸润白细胞； 3）将tils的转录组与自体外围细胞或来自KS不对称对照的人。从这些比较调查中，我们预计对表达的理解有更强烈的理解 KS肿瘤生态位适应性免疫细胞的程序和免疫调查性和更完整的了解HIV-1的作用，免疫抑制，反感，疲惫和敏感利基。这种理解将指导介入策略，包括免疫治疗剂的设计和潜在的疫苗针对KS。