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

(PQ 6) KSHV 肿瘤发生和 KS 免疫环境的新模型

基本信息

批准号：
10737765
负责人：
ETHEL CESARMAN
金额：
$ 23.9万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737765
关键词：
3-Dimensional AIDS related cancer Acquired Immunodeficiency Syndrome Address Affect Africa South of the Sahara Animals Antibody Therapy Attention B-Lymphocytes Biopsy Blood Vessels CD4 Positive T Lymphocytes CD8B1 gene Cell Line Cells Chronic Clinical Complement 3d Cytometry Detection Development Disease Drug Targeting Elements Endothelial Cells Engineering Environment Etiology Evaluation Gene Expression Genes Genetically Engineered Mouse Goals Grant Growth HIV Human Human Herpesvirus 8 Hydrogels Image Immune Immunocompetent Immunodeficient Mouse Immunotherapy Implant In Vitro Individual Infection Inflammatory Inflammatory Infiltrate Kaposi Sarcoma Laboratories Lead Lesion Lymphoma Lymphoproliferative Disorders Lytic Macrophage Malignant Neoplasms Messenger RNA Methods Modeling Multicentric Angiofollicular Lymphoid Hyperplasia Mus Organoids Pathogenesis Pathology Patients Pattern Permeability Persons Pharmaceutical Preparations Phenotype Plasma Cells Process Proteins Research Rodent Role Schedule Signal Transduction Solid System T-Cell Depletion Testing Therapeutic Tissues Transcript Translating Translations Tumor Biology Viral Genes Viral Genome Viral Proteins Virus Virus Latency Xenograft procedure candidate identification checkpoint therapy chemotherapy common treatment histogenesis human disease immune cell infiltrate immunoregulation immunosuppressed in vivo in vivo Model mast cell mouse model neoplastic cell novel novel therapeutics organ transplant recipient pre-clinical primary effusion lymphoma resistance mechanism response targeted treatment therapeutic evaluation tumor tumor microenvironment tumor-immune system interactions tumorigenesis

项目摘要

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.

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受到了广泛的关注，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。