(PQ 6) New Models of KSHV Oncogenesis and KS Immune Environment

项目总结 卡波西肉瘤(KS)是全球艾滋病毒携带者最常见的癌症，也是撒哈拉以南非洲最常见的癌症之一，由卡波西肉瘤疱疹病毒(KSHV，又称HHV-8)感染引起。该病毒还可引起原发性渗出性淋巴瘤(PEL)和多中心性Castleman病(MCD)。虽然PEL很罕见，但它是一种侵袭性的恶性肿瘤，几乎没有治疗选择。KSHV相关疾病很难建模，因为这种病毒具有物种特异性，它不会在培养中转化细胞，体外感染经常导致潜伏和裂解病毒基因的混合表达，而且相关的动物病毒不会引起相同的病理变化。此外，KS病变由多种细胞组成，包括潜伏感染KSHV的梭形细胞和包括大量CD8+和CD4+T细胞、浆细胞、巨噬细胞和肥大细胞的混合炎性浸润物。虽然梭形细胞的组织发生已经引起了人们的广泛关注，但对KS病变中的免疫浸润物的描述还很肤浅和不完整。该应用的首要目标是开发KSHV相关疾病的体外、体外和体内临床前模型，包括KS、MCD和淋巴瘤。为了建立KS模型，我们将应用对人类损伤的观察，并包括这种疾病的免疫元素。这将通过以下特定目标实现：1)主要潜伏期转录基因在免疫活性小鼠中的有条件表达；2)检测患者KS病变中的肿瘤免疫环境，并测试主要免疫亚群在小鼠中的作用；以及3)设计合成的、体外和体外的Kaposi肉瘤样组织生态位，以控制健康和患病的初级内皮细胞的生长。我们将在这些模型中检查一线治疗方法、靶向治疗和免疫治疗的效果，以验证它们在临床前的应用。

PROJECT SUMMARY Kaposi's sarcoma (KS) is the most common cancer globally in people living with HIV, and among the most common cancers in Sub-Saharan Africa, and is caused by infection by the Kaposi sarcoma herpesvirus (KSHV, also called HHV-8). This virus also causes primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). While PEL is rare, it is an aggressive malignancy with few therapeutic options. KSHV-associated diseases are difficult to model because this virus is species-specific, it does not transform cells in in culture, in vitro infection frequently leads to a mixture of latent and lytic viral gene expression, and related animal viruses do not cause the same pathologies. Furthermore, KS lesions are composed of a mixture of cells that include latently KSHV-infected spindle cells and a mixed inflammatory infiltrate that includes numerous CD8+ and CD4+ T cells, plasma cells, macrophages, and mast cells. While substantial attention has been given to the histogenesis of the spindle cells, the immune infiltrates in KS lesions have only been superficially and incompletely described. The overarching goal is this application is develop preclinical in vitro, ex vivo and in vivo models of KSHV-associated diseases, including KS, MCD and lymphoma. To model KS, we will apply observations from human lesions, and include the immune elements of this disease. This will be accomplished through the following specific aims: 1) conditional expression of major latency transcript genes in immunocompetent mice; 2) examine the tumor immune environment in KS lesions in patients and test the role of major immune subsets in mice; and 3) engineer synthetic, in vitro and ex vivo Kaposi sarcoma-like tissue niches for controlled growth of healthy and diseased primary endothelial cells. We will examine the effects of first line therapeutic approaches, targeted therapy and immunotherapy in these models to validate them for preclinical use.