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KSHV,HIV and the Kaposi's Sarcoma Tumor Niche

KSHV、HIV 和卡波西肉瘤肿瘤位

基本信息

批准号：
10424452
负责人：
John T West
金额：
$ 54.01万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10424452
关键词：
AIDS with Kaposi&apos 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

项目摘要

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