KSHV,HIV and the Kaposi's Sarcoma Tumor Niche

KSHV、HIV 和卡波西肉瘤肿瘤位

• 批准号: 10530977
• 负责人: John T West
• 金额: $ 1.04万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10530977
• 关键词: KSHV; HIV; Kaposi; Sarcoma; Tumor

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。