Abramson Cancer Center Support Grant

艾布拉姆森癌症中心支持补助金

基本信息

批准号：
10362833
负责人：
ROBERT H VONDERHEIDE
金额：
$ 12.46万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-01-15 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10362833
关键词：
Abramson Cancer Center at the University of Pennsylvania Address Adult Area Automobile Driving Basic Science Beverages Breast Cancer Burden Cancer Center Cancer Center Support Grant Cancer Control Cancer Patient Capital Caring Catchment Area Cause of Death Cells Cellular biology Child Clinical Clinical Data Clinical Investigator Clinical Protocols Clinical Research Clinical Sciences Clinical Trials Collaborations Colorectal Community Outreach Comprehensive Cancer Center Country County DNA Damage Delaware Development Diagnosis Disease Early Diagnosis Ecosystem Enrollment Epigenetic Process Face Fostering Funding Genetic Geography Health Policy Health Services Research Health behavior Hospitals Human Papilloma Virus Vaccination Immunology Immunotherapy Incidence Intervention Trial Journals Laboratories Laboratory Research Leadership Lung Lymphoma Malignant Childhood Neoplasm Malignant Neoplasms Manuscripts Medicine Mission Modernization Monitor Nature New Jersey Oncogenes Paper Patients Pediatric Hospitals Pennsylvania Philadelphia Population Population Research Population Sciences Prevention Prostate Protocols documentation Proton Radiation Publications Publishing Recording of previous events Research Research Personnel Resource Sharing Resources Rest Risk Risk Assessment Risk Factors Science Scientist Smoking System T-Lymphocyte Training and Education Translating Translational Research Translations Underrepresented Populations United States United States National Institutes of Health Universities Vision anticancer research base behavioral economics brca gene cancer care cancer education cancer risk cancer surgery chimeric antigen receptor T cells clinical investigation clinical practice community engagement data management environmental toxicology ethnic diversity gene therapy health care delivery improved innovation melanoma member microbiome molecular imaging novel strategies novel therapeutic intervention outreach patient oriented population based prevent programs proton therapy public health relevance radiomics response smoking cessation survivorship targeted treatment tobacco control translational scientist treatment trial tumor metabolism tumor microenvironment

项目摘要

Cancer is the leading cause of death in people living with HIV (PLWH) in the United States and worldwide despite combination antiretroviral therapy (cART). Although the incidences of AIDS-defining malignancies have declined since the advent of cART, a number of non-AIDS–defining cancers (NADCs) appear more common in HIV-1–infected individuals relative to the general population. Hodgkin’s lymphoma (HL) represents one of the most common types of NADCs that occurs in HIV-infected individuals. The incidence of HL is 10-fold higher in PLWH relative to the general population, and the frequency of this malignancy is actually increasing in the postcART era. Several factors are associated with the rising rate in HL, but two key features are accelerated immunological aging and HIV infection, suggesting that there is interplay between HIV and immune senescence that results in an escalating occurrence of cancer development and progression. We and others have identified specific epigenetic changes associated with aberrant T cell replicative capacity that are also altered in cancer, chronic viral infection, inflammatory diseases and aging. Published work, together with our preliminary singlecell RNA sequencing studies suggest that CD8+ T cells responsible for tumor control in HL exhibit several abnormalities, including a more advanced differentiation state, poor proliferative capacity and downregulation of several genes that negatively regulate cellular senescence. The presence of a characteristic inflammatory microenvironment is a fundamental component of the tumor mass and an essential pathogenic factor in HL. In chronic HIV infection, a similar accumulation of senescent and activated CD8+ T cells and increasing levels of inflammatory factors are linked to higher risks of morbidity and mortality, indicating that specific disease processes (e.g., inflammation) likely underlie HIV-associated epigenetic changes and concomitant immunosenescence. Thus, HIV and lymphoma may have an additive influence on overlapping epigenetic pathways to accelerate aging-induced immune deterioration, resulting in loss of tumor control. However, important gaps exist in our understanding of the fundamental nature and underlying mechanisms of T cell senescence in HIV and cancer, and how those in turn, influence anti-tumor immunity; this hampers our practical ability to clinically manage these diseases and develop new effective therapies. This pilot proposal is responsive to the NIH HIV/AIDS Research High Priorities (as listed in NOT-OD15-137) through expansion of knowledge regarding the impact of pre-mature immunological aging in long-term HIV disease and the pathogenesis of NADCs. Our approach benefits from a longstanding interest in cellular immunology and determining the molecular underpinnings of age-induced immune decline in the setting of oncogenesis, tumor progression and therapeutic responses. In this vein, we recently established and operationalized a pipeline that incorporates cutting-edge transcriptional and epigenetic profiling of T cells and tissues from cancer patients and age/gender-matched healthy controls. The experiments we propose will investigate the relationship between HIV infection, cancer, immunological aging and how the health of CD8+ T cells might be related to specific epigenetic alterations. Our overall goals are to understand how chronic HIVinfection in HL contributes to the process of immunosenescence, determine the impact of epigenetic features on immune cell phenotype as well as function and identify the pathways responsible for such changes. The central hypothesis of this proposal is that CD8+ T cell immunosenecence is accelerated in HIV+ HL due to an additive pro-inflammatory environment that alters memory CD8+ T cell differentiation, homeostasis and function through epigenetic regulation of gene expression. The above hypothesis is based on findings that numerous malignancies have been attributed to epigenetic and transcriptional aberrations; these changes contribute to immune dysfunction in both chronic HIV infection and cancer. Our Specific Aims are: Aim 1. To examine the impact of HL and HIV infection on immune aging as it relates to CD8+ T cell differentiation state, telomere length, p16INK4A levels and T cell receptor (TCR) repertoire diversity in age/gender-matched cohorts of HL and HIV+ HL patients, relative to HIV- (healthy donors) and HIV+ subjects. Aim 2. To characterize the epigenetic and transcriptional landscapes of CD8+ T cells in cART-treated HIV+ HL patients using a novel pipeline that incorporates digital spatial profiling, bulk sequencing and single-cell analyses of biological samples, including cancer tissues. Both aims will explore associations between various immunosenecence signatures and levels of inflammation, immune activation and dysfunction in HIV+ HL.

癌症是美国和全球目的地组合抗逆转录病毒疗法（CART）的艾滋病毒（PLWH）患者的主要死亡原因。尽管自推车前进以来，艾滋病定义的恶性肿瘤的发动机已经下降，但许多非AIDS定义的癌症（NADC）在与普通人群相对于HIV-1感染的个体中似乎更为常见。霍奇金的淋巴瘤（HL）代表了HIV感染者中最常见的NADC类型之一。相对于普通人群，PLWH的HL事件高10倍，并且这种恶性肿瘤的频率实际上在oftcart时代增加。多个因素与HL的速率上升有关，但是两个关键特征是加速免疫学衰老和HIV感染，这表明HIV和免疫敏感之间存在相互作用，这导致我们和其他人的发生升级，我们和其他人已经确定了与异常的T细胞重复能力相关的特定表观变化，这也会改变癌症，慢性病毒性，慢性病毒性感染，肥胖，肿瘤也会改变。发表的工作以及我们的初步单核RNA测序研究表明，负责HL肿瘤控制的CD8+ T细胞暴露了几种异常，包括更先进的分化状态，较差的增殖能力和几种负面调节细胞敏感的基因的下调。特征性炎症微环境的存在是肿瘤质量的基本成分，也是HL中基本的致病因素。在慢性艾滋病毒感染中，感觉和激活的CD8+ T细胞的类似积累以及炎症因子水平的增加与更高的发病率和死亡率有关，表明特定疾病过程（例如感染）可能是与HIV相关的表观遗传变化和同步免疫的基础。这是HIV和淋巴瘤可能会对重叠的表观遗传途径产生额外的影响，以加速衰老诱导的免疫端内化，从而导致肿瘤控制丧失。然而，我们对艾滋病毒和癌症中T细胞感应的基本性质和潜在机制的理解中存在重要的差距，以及这些又如何影响抗肿瘤免疫学；这阻碍了我们在临床管理这些疾病并开发新有效疗法的实际能力。该试点提案对NIH HIV/AIDS研究的高度重视有反应（如NOT-OD15-137中列出），通过扩大有关成熟预性免疫老化对长期HIV疾病的影响和NADC的发病机理的影响。我们的方法受益于对细胞免疫学的长期兴趣，并确定在肿瘤发生，肿瘤进展和治疗反应的环境下，年龄诱导的免疫学下降的分子基础。在这种情况下，我们最近建立了一条管道，该管道结合了癌症患者的T细胞和组织的尖端转录和表观遗传分析以及年龄/性别匹配的健康对照。我们提出的实验将研究HIV感染，癌症，免疫老化以及CD8+ T细胞的健康如何与特定的表观遗传改变有关。我们的总体目标是了解HL中的慢性Hivintection如何促进免疫的过程，确定表观遗传特征对免疫球体表型以及功能的影响，并确定负责此类变化的途径。该建议的中心假设是，由于额外的促炎环境，CD8+ T细胞在HIV+ HL中加速了免疫力，从而改变了记忆CD8+ T细胞分化，体内平衡和功能通过基因表达的表观遗传调节而改变。上述假设是基于发现，许多恶性肿瘤归因于表观遗传和转录畸变。这些变化导致慢性HIV感染和癌症的免疫功能障碍。我们的具体目的是：目的1。检查HL和HIV感染对与CD8+ T细胞分化状态，端粒长度，p16INK4A水平和T细胞受体（TCR）相对HL和HIV+ HL患者的年龄/性别匹配群体中的性别多样性，与HIV+ HIV（HIV-HIV）相对+++ HIV+ HIV+ HIV+ HIV+ HIV+ HIV+ HIV+ HIV+ HIV+ HIV+ HIV+ HIV患者的影响。目的2。使用一种新型管道来表征CD8+ T细胞在CD8+ T细胞中的表观遗传和转录景观，使用新型管道结合了数字空间分析，批量测序和包括癌症组织在内的生物样品的单细胞分析。这两个目标都将探索各种免疫特征和炎症水平，HIV+ HL中免疫激活和功能障碍之间的关联。