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Characterization of a T cell dysfunctional state induced in mice with AML

AML 小鼠中诱导的 T 细胞功能障碍状态的表征

基本信息

批准号：
8276690
负责人：
JUSTIN P. KLINE
金额：
$ 32.73万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8276690
关键词：
Acute Myelocytic Leukemia Address Agonist Animal Model Antigens Apoptotic Belief Biological Blood Circulation Bone Marrow CD8B1 gene Cancer Immunology Science Cell Line Cells Cessation of life Clinical Conceptions Confocal Microscopy Cross Presentation Data Dendritic Cells Dendritic cell activation Development Dissection Elements Engineering Functional disorder Future Generations Goals Growth Hematogenous Immune Immune Tolerance Immune system Immunity Immunofluorescence Microscopy Immunotherapeutic agent Immunotherapy Interleukin-7 Knowledge Label Laboratories Lead Lymphoid Malignant Neoplasms Mediator of activation protein Modeling Mus Nature Organ Outcome Patients Pattern Phagocytosis Poly I-C Population Process Regulation Research Signal Transduction Solid T cell anergy T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte TNFRSF5 gene Testing Toll-like receptors Transgenic Organisms Translations Tumor Antigens Work base cancer cell cell type clinically relevant in vivo leukemia lymph nodes pre-clinical prevent reconstitution research study subcutaneous tumor

项目摘要

DESCRIPTION (provided by applicant): The initial activation of tumor antigen-specific T cells is regulated by host dendritic cells (DC). Recently, it has been observed that "danger signals" produced by dying cancer cells activate local host DC, which are then able to prime adaptive anti-tumor T cell responses. These observations have clarified our understanding of how tumor antigen-specific T cells are activated against cancers which grow as a solid mass. However, the processes which govern the activation versus suppression of tumor antigen-specific T cells in hosts with hematological cancers, which grow in a disseminated pattern and lack a classical "draining" lymph node, remain elusive. The long-term goal of our laboratory is to unravel these mechanisms at a basic level, which we believe will be important to guide the development of effective immunotherapy for leukemia in the future. Our work in a murine acute myeloid leukemia (AML) model has revealed that when leukemia cells are introduced into mice intravenously (IV), antigen-specific T cell dysfunction rapidly ensues, whereas a subcutaneous (SC) AML cell inoculation leads to successful T cell priming, arguing that a fundamental difference exists between the ability of hematological versus solid cancers to activate the host immune system. Thus, we hypothesize that a state of antigen-specific T cell dysfunction, consistent with T cell anergy or deletion, occurs in hosts with AML, which is induced by tolerogenic DC, and propose the following Specific Aims: (1) To identify the mechanism of antigen-specific T cell dysfunction induced in a murine AML model; (2) To identify the cellular mediators of T cell dysfunction in mice with AML; and (3) to identify strategies targeting activation of host DC to prevent or reverse T cell dysfunction in mice with AML. To address these aims, we have generated a pre-clinical AML model. The C1498 murine AML cell line has been engineered to express a model antigen which is recognized by a T cell receptor transgenic CD8+ T cell (2C). The proliferation and function of 2C T cells in mice following IV versus SC C1498 cell inoculation will be carefully analyzed to identify the mechanism of T cell dysfunction. To identify the cell(s) which may regulate T cell dysfunction, fluorescently-labeled C1498 cells will be inoculated IV into mice, and immunofluorescence and confocal microscopy will be utilized to identify which DC subset(s) engulf dying C1498 cells in secondary lymphoid organs. Specific DC populations will then be targeted for depletion to determine which is ultimately responsible for inducing T cell dysfunction in mice with AML. Lastly, clinically-relevant strategie targeting host DC activation will be explored to determine which can reverse T cell dysfunction in mice with AML. These studies will contribute to our understanding of how hematological cancers promote immune evasion. Additionally, approaches targeting the reversal of immune tolerance will be tested, possibly leading to strategies useful for clinical translation. Thus, the knowledge to be gained is important from a biological standpoint, and also is expected to lead to immunotherapeutic approaches for patients with AML in the future. PUBLIC HEALTH RELEVANCE: The regulation of T cell activation versus tolerance against cancers which grow in the circulation, such as acute myeloid leukemia (AML), has been under-explored. Our research group has observed that T cells which recognize leukemia cells become rapidly dysfunctional in an animal model of AML. It is hypothesized that this T cell dysfunction results from dendritic cells in the host which present antigens to T cells in a context unfavorable for T cell activation, leading to tolerance. In this proposal, the mechanism of T cell tolerance an its underlying regulation will be clarified, and clinically-relevant strategies targeting the reveral of this phenomenon will be explored, which if successful, could lead to the development of efficacious immunotherapy for AML patients in the future.