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.

项目概要流行性卡波西肉瘤 (KS) 是一种 HIV-1 相关肿瘤，并且仍然是发病率最高的肿瘤之一尽管抗逆转录病毒治疗（ART）计划有效，但撒哈拉以南非洲男性和女性仍存在肿瘤。驱动 KS 的根本机制似乎是 KSHV 感染，但很明显，仅 KSHV 感染不足以发展 KS，因为大多数感染者不会发展为 HIV-1 合并感染或 KS。免疫抑制如何诱发、加剧或加速 KS 疾病。与 KSHV 协同形成或维持肿瘤生态位在组织中很大程度上尚未被探索。在许多癌症中，清楚地了解肿瘤微环境，包括存在、抗原- 肿瘤浸润淋巴细胞（TIL）的特异性和功能性正在彻底改变治疗方法。然而，对于 KS，我们缺乏有关 TIL 性质以及肿瘤微环境是否与 TIL 相关的信息。正在以 HIV-1 依赖性方式抑制其抗肿瘤功能。该项目旨在纠正这一问题。通过比较调查，了解病例 (HIV-1+/KS+) 与对照 ((HIV-1+/KS-) 设计中的知识差距与外周免疫系统中相同细胞相比，TIL 的表型和功能并通过比较肿瘤和外周免疫细胞的表达模式。我们的假设是，即使面对可检测到的 KSHV 反应性外周 T 细胞反应和有效性 HIV-1 抑制，KSHV Ag 特异性肿瘤浸润 T 淋巴细胞 (TIL) 数量不足并且这些细胞对 KS 肿瘤中的抗原没有反应。我们的方法是 1) 进行功能比较。外周 CD4 和 CD8 T 细胞对 KSHV 和 KS 中普遍存在的免疫显性抗原的反应区分 HIV-1 病程；2) 分离 KS，并对其进行免疫表型和功能表征肿瘤浸润白细胞；3) 比较 TIL 与自体外周细胞的转录组或那些来自堪萨斯州无症状对照的人。从这些比较研究中，我们期望对表达式有更深入的理解 KS 肿瘤生态位中适应性免疫细胞的程序和免疫反应性以及更完整了解 HIV-1、免疫抑制、无能、疲惫和衰老在定义中的作用这种理解将指导干预策略，包括免疫治疗和治疗的设计。针对 KS 的潜在疫苗。