Deciphering Tumor-T cell Interactions in HIV-associated Diffuse Large B-cell Lymphoma (Biospecimens/Biocohort)

解读 HIV 相关弥漫性大 B 细胞淋巴瘤中肿瘤与 T 细胞的相互作用（生物样本/生物队列）

• 批准号: 10618592
• 负责人: H. Shelton Earp
• 金额: $ 7.02万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618592
• 关键词: Address; Antigens; Antitumor Response; Appearance; Architecture; B lymphoid malignancy; B-Cell Lymphomas; B-Lymphocytes; Biological; Biological Factors; Biological Markers; Biological Models; Blood; Cancer Etiology; Cell Communication; Cell physiology; Cells; Cessation of life; Characteristics; Chronic; Clinical; Collaborations; Cytometry; DNA; Development; Diagnosis; Epidemic; Epitopes; Evolution; Frequencies; Gene Expression; Goals; HIV; HIV Infections; HIV Seronegativity; HIV Seropositivity; HIV antiretroviral; HIV therapy; Heterogeneity; Histology; Human; Immune; Immune System Diseases; Immune response; Immunocompetent; Immunogenomics; Immunotherapy; Individual; Infection; Inferior; Influentials; Knowledge; Lymphoma; Lymphomagenesis; Maintenance; Malawi; Malignant Neoplasms; Maps; Mediating; Mutation; Outcome; Patient Selection; Patient-Focused Outcomes; Patients; Persons; Population; Positioning Attribute; Role; Sampling; Spatial Distribution; T cell receptor repertoire sequencing; T cell response; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; T-cell receptor repertoire; Techniques; Technology; Testing; Tissue Banks; Tissue-Specific Gene Expression; Tissues; Treatment-related toxicity; Tumor Antigens; UNC Lineberger Comprehensive Cancer Center; Ursidae Family; Vascular Proliferation; Viral; Work; antiretroviral therapy; base; bioinformatics pipeline; biomarker discovery; chemotherapy; cohort; comparative; effector T cell; exhaust; exhaustion; exome sequencing; experience; host neoplasm interaction; immune function; immunogenicity; improved; improved outcome; innovation; intercellular communication; large cell Diffuse non-Hodgkin' s lymphoma; macrophage; multiplexed imaging; neoantigens; new therapeutic target; novel; patient response; peripheral blood; personalized therapeutic; pressure; response; restoration; therapeutic target; transcriptome; treatment strategy; tumor; tumor growth; tumor microenvironment

ABSTRACT Diffuse Large B-cell Lymphoma (DLBCL) is highly associated with HIV and the commonest cause of cancer death among HIV-infected individuals. However, outcomes remain sub-optimal with multiagent chemotherapy. Promising immunotherapies are available, but the tumor-host interactions in DLBCL are poorly understood, even outside the HIV context. Addressing this gap in knowledge is necessary for patient selection, biomarker discovery, and for development of new treatment strategies. However, human studies to date have been limited by the lack available advanced technologies applied to appropriate patient cohorts. Our long-term goal is to improve outcomes for HIV-associated DLBCL by deciphering the diversity, functional heterogeneity, and spatial distribution of effector T-cells within the tumor microenvironment (TME). In this proposal, we utilize DLBCL spontaneously arising in HIV-positive/antiretroviral therapy (ART)-naïve, HIV-positive/ART- experienced, and HIV-negative patients as a comparative model system to investigate the anti-tumor T-cell response on lymphomagenesis. With existing collaborations, our access to a clinically annotated DLBCL sample biocohort from HIV- and ART treated and un-treated HIV+ patients, and advanced technologies, we are in a unique position to characterize and map the T-cell response. To address our goal, we will use highly- multiplexed imaging mass cytometry to characterize the topology of functional T-cell subsets within the TME of DLBCL, perform immune sequencing to study the T-cell receptor (TCR) repertoire characteristics in the TME and peripheral blood, and identify neoantigenic targets using a novel bioinformatic pipeline. The goals of this project are enabled by our existing work in Malawi, where, given the generalized HIV epidemic, comparisons within specific tumor types based on HIV status are uniquely possible. The proposed work is necessary to understand the biological factors underlying lymphomagenesis and improve survival for HIV-associated DLBCL.

抽象的 弥漫性大 B 细胞淋巴瘤 (DLBCL) 与 HIV 高度相关，也是最常见的癌症原因 然而，多药化疗的结果仍然不理想。 有前景的免疫疗法是可用的，但 DLBCL 中肿瘤与宿主的相互作用却知之甚少。 即使在艾滋病毒背景之外，解决这一知识差距对于患者选择、生物标志物也是必要的。 然而，迄今为止的人体研究尚未取得进展。 由于缺乏适用于适当患者群体的可用先进技术而受到限制。 目标是通过破译多样性、功能异质性、 在此提案中，我们利用了效应 T 细胞在肿瘤微环境 (TME) 中的空间分布。 在 HIV 阳性/抗逆转录病毒治疗 (ART) 未接受过治疗、HIV 阳性/ART- 中自发出现 DLBCL 经验丰富的HIV阴性患者作为比较模型系统来研究抗肿瘤T细胞 通过现有的合作，我们获得了临床注释的 DLBCL。 我们从接受过 HIV 和 ART 治疗和未接受治疗的 HIV+ 患者中采集生物队列样本，并采用先进技术 处于表征和绘制 T 细胞反应图谱的独特位置。为了实现我们的目标，我们将使用高度- 多重成像质谱流式分析仪表征 TME 内功能性 T 细胞亚群的拓扑结构 DLBCL，进行免疫测序以研究 TME 中的 T 细胞受体 (TCR) 库特征 和外周血，并使用新型生物信息管道识别新抗原靶标。 该项目是通过我们在马拉维的现有工作实现的，考虑到艾滋病毒的普遍流行，比较 基于 HIV 状态的特定肿瘤类型是唯一可能的。 了解淋巴瘤发生的生物学因素并提高 HIV 相关患者的生存率 弥漫大B细胞淋巴瘤。