KSHV, HIV and the Kaposi's Sarcoma Tumor Niche

KSHV、HIV 和卡波西肉瘤肿瘤位

• 批准号: 10219188
• 负责人: John T West
• 金额: $ 4.97万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219188
• 关键词: AIDS with Kaposi' s sarcoma; Acquired Immunodeficiency Syndrome; African; American; Antigens; Antineoplastic Agents; Autologous; Automobile Driving; B-Lymphocytes; Biopsy; CD14 gene; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCL9 gene; Cells; Chemotactic Factors; Collaborations; Communities; Cytomegalovirus; Data; Defect; Development; Diagnosis; Disease; Effector Cell; Environment; Etiology; Evaluation; Expression Profiling; Failure; HIV; HIV-1; Herpesviridae Infections; Human Herpesvirus 4; Human Herpesvirus 8; Iatrogenesis; Immune; Immune system; Immunity; Immunodominant Antigens; Immunologics; Immunophenotyping; Immunosuppression; Immunotherapeutic agent; Incidence; Individual; Inflammatory; Influenza; Interleukin-10; Intervention; Investigation; Kaposi Sarcoma; Knowledge; Leukocytes; Malignant Neoplasms; Memory; Molecular; Nature; Neoplasms; Patients; Pattern; Peptides; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Population; Process; Resected; Role; Skin; Specificity; Suspensions; T cell differentiation; T cell response; T-Lymphocyte; Teaching Hospitals; Testing; Therapeutic; Tissues; Tumor Tissue; Tumor-Infiltrating Lymphocytes; Universities; Vaccines; Viral; Woman; Zambia; anergy; antiretroviral therapy; checkpoint inhibition; co-infection; comparative; cytokine; design; exhaustion; illness length; immune reconstitution; macrophage; men; neoplastic; patient stratification; programs; response; senescence; transcriptome; transcriptome sequencing; tumor; tumor microenvironment

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.

项目总结 流行性卡波西肉瘤(KS)是一种与HIV-1相关的肿瘤，仍是发病率最高的肿瘤之一 尽管抗逆转录病毒治疗(ART)计划有效，撒哈拉以南非洲男性和女性的肿瘤仍在增加。 KS的根本机制似乎是KSHV感染，但很明显，KSHV单独感染 对于KS的发展是不够的，因为大多数感染者不会发展KS。HIV-1混合感染或 治疗性免疫抑制可诱发、加重或加速KS疾病。HIV-1如何合并感染 与KSHV协同作用形成或维持肿瘤生态位在很大程度上是组织中未被探索的。 在许多癌症中，对肿瘤微环境的清楚了解，包括存在，抗原- 肿瘤浸润性淋巴细胞(TILs)的特异性和功能性正在彻底改变治疗方法。 然而，对于KS，我们缺乏关于TIL的性质以及肿瘤微环境是否 以HIV-1依赖的方式抑制它们的抗肿瘤功能。这个项目试图纠正这一点 病例(HIV-1+/KS+)与对照((HIV-1+/KS-)设计中的知识差距比较研究 TIL的表型和功能与外周免疫系统中相同细胞的比较 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 抑制HIV-1，KSHV抗原特异性肿瘤浸润性T淋巴细胞(TIL)数量不足 在KS肿瘤中，这些细胞对抗原没有反应。我们的方法是1)在功能上比较 KS患者外周血中CD4、CD8T细胞对KSHV及无处不在的免疫优势抗原的反应 不同的HIV-1病程；2)KS的分离、免疫表型和功能鉴定 肿瘤浸润性白细胞；3)将TIL的转录本与自体外周细胞或 KS无症状对照。 从这些比较研究中，我们预计会对这一表达有更有力的理解 获得性免疫细胞在KS肿瘤生态位中的程序和免疫反应性 了解HIV-1、免疫抑制、无能、衰竭和衰老在定义这一过程中的作用 利基市场。这一理解将指导干预策略，包括免疫疗法的设计和 潜在的针对KS的疫苗。