KSHV, HIV and the Kaposi's Sarcoma Tumor Niche

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。

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.