(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

• 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
• 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

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.

项目摘要 卡波西肉瘤（KS）是全球艾滋病毒感染者中最常见的癌症，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，也称为HHV-8）感染引起。这种病毒也引起原发性渗出性淋巴瘤（PEL）和多中心Castleman病（MCD）。虽然PEM很少见，但它是一种侵袭性恶性肿瘤，治疗选择很少。KSHV相关疾病难以建模，因为这种病毒是种特异性的，它在培养中不转化细胞，体外感染经常导致潜伏和裂解病毒基因表达的混合物，并且相关动物病毒不会引起相同的病理。此外，KS病变由细胞混合物组成，包括潜伏性KSHV感染的梭形细胞和混合的炎性浸润物，包括大量的CD8+和CD4 + T细胞、浆细胞、巨噬细胞和肥大细胞。虽然梭形细胞的组织发生已经引起了很大的关注，但KS病变中的免疫浸润仅被表面和不完全地描述。总体目标是本申请开发KSHV相关疾病（包括KS、MCD和淋巴瘤）的临床前体外、离体和体内模型。为了模拟KS，我们将应用来自人类病变的观察结果，并包括这种疾病的免疫因素。这将通过以下具体目标来实现：1）免疫活性小鼠中主要潜伏转录物基因的条件表达; 2）检查患者KS病变中的肿瘤免疫环境并测试小鼠中主要免疫亚群的作用;以及3）工程化合成的体外和离体卡波西肉瘤样组织小生境，用于健康和患病原代内皮细胞的受控生长。我们将研究一线治疗方法，靶向治疗和免疫治疗在这些模型中的作用，以验证它们的临床前使用。