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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.

项目摘要流行性卡波西肉瘤（KS）是一种HIV-1相关的肿瘤，并且仍然是最高发病率之一尽管有有效的抗逆转录病毒治疗（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，KSHV感染单独对于KS发展是不够的，因为大多数感染个体不发展KS。HIV-1合并感染或治疗性免疫抑制诱导、加重或加速KS病。HIV-1合并感染与KSHV协同形成或维持肿瘤小生境的肿瘤细胞在组织中基本上未被探索。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革新治疗方法。然而，对于KS，我们缺乏关于TILs性质的信息，以及肿瘤微环境是否以HIV-1依赖的方式抑制其抗肿瘤功能。本项目旨在纠正这一点通过比较研究设计病例组（HIV-1+/KS+）与对照组（HIV-1+/KS-）知识差距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细胞反应和有效的 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肿瘤中的抗原无应答。我们的方法是1）功能比较 KS患者外周血CD 4和CD 8 T细胞对KSHV和普遍免疫显性抗原的应答差异HIV-1疾病持续时间; 2）分离、免疫表型和功能表征KS 肿瘤浸润性白细胞;和3）将TIL的转录组与自体外周细胞或来自KS无症状对照的那些。从这些比较研究中，我们预计会对表达方式有更深入的了解。程序和适应性免疫细胞在KS肿瘤生态位的免疫反应，更完整理解HIV-1、免疫抑制、无反应性、衰竭和衰老在定义利基这种理解将指导干预策略，包括免疫治疗剂的设计，可能是针对KS的疫苗。