The role of myeloid suppressor cells in tumor-specific tolerance

骨髓抑制细胞在肿瘤特异性耐受中的作用

基本信息

批准号：
7676240
负责人：
Ivan M. Borrello
金额：
$ 33.6万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7676240
关键词：
Accounting Antigens Apoptosis Attention Autologous Transplantation Bone Marrow Transplantation CD4 Positive T Lymphocytes CD8B1 gene Cell physiology Data Development Environment Event Generations Genes Hematologic Neoplasms Hematopoietic Immune Immune response Immunity Immunosuppression Immunotherapy Kinetics Laboratories Liquid substance Lymphoma Malignant Neoplasms Measurable Mediating Modeling Molecular Mus Myelogenous Nitric Oxide Nitric Oxide Synthase Pathway interactions Patients Pharmaceutical Preparations Phenotype Population Production Role Solid Neoplasm Suppressor-Effector T-Lymphocytes T-Cell Receptor T-Lymphocyte Testing Therapeutic Transgenic Model Transplantation Tumor Antigens Tumor Burden Tumor Immunity Vaccination Viagra Work abstracting advanced disease anergy arginase base cancer immunotherapy inhibitor/antagonist mouse model response sildenafil tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Limitations to effective immunotherapy are increasingly being recognized. Specifically, a number of regulatory/ suppressive pathways have been identified that present significant barriers to the tumor antigens in cancer-bearing hosts. Amongst these, myeloid suppressor cells (MSCs) are directly associated with increasing tumor burdens and exert their inhibitory effects through the production of nitric oxide and arginase-1. In this proposal, we seek to: 1) determine the relationship between the generation of MSCs and the development of antigen-specific T cell tolerance in a T cell receptor transgenic model with specific attention to paid to the inter-relationship between MSCs and Tregs. 2) examine the role of MSCs during tumor progression in hematologic malignancies. 3) examine the role of bone marrow transplantation in MSC turnover and develop strategies to overcome MSC- mediated immunosuppression. Specifically, we will study the role of IL4Ra+ MSCs utilizing the LysMcre IL4Ra+flox mice in immunosuppression. We will also examine the role of PDE5 inhibitors such as sildenafil in abrogating MSC function and test various therapeutic conditions in an effort to maximize antitumor immunity. Lay abstract: A major barrier to effective anti-cancer immunotherapy is the ability to mount a clinically meaningful anti- tumor response. To do so, the host must be capable of overcoming the intrinsic suppressive mechanisms that limit the development of effective immune responses. One such mechanism is the generation of myeloid suppressor cells (MSCs) that increase with increasing tumor burden and inhibit immune responsiveness. To date, most of the work in this field has focused on their role in solid tumors. Here, we propose to examine the effect of MSCs in mouse models of liquid tumors- namely lymphoma. We will also attempt to determine how bone marrow transplantation impacts on MSC function and turnover. Lastly, we will attempt to develop strategies to reduce MSC function in the transplant setting through the use of Viagra and related drugs based on our recent observations that these drugs can effectively inhibit MSC function.

描述（由申请人提供）：人们越来越认识到有效免疫疗法的局限性。具体来说，已经确定了许多调节/抑制途径，这些途径对患有癌症的宿主中的肿瘤抗原存在显着的障碍。其中，骨髓抑制细胞 (MSC) 与肿瘤负荷增加直接相关，并通过产生一氧化氮和精氨酸酶-1 发挥其抑制作用。在本提案中，我们寻求：1）确定T细胞受体转基因模型中MSC的产生与抗原特异性T细胞耐受性的发展之间的关系，特别关注MSC和Treg之间的相互关系。 2) 检查间充质干细胞在血液恶性肿瘤的肿瘤进展过程中的作用。 3) 检查骨髓移植在 MSC 周转中的作用并制定克服 MSC 介导的免疫抑制的策略。具体来说，我们将利用 LysMcre IL4Ra+flox 小鼠研究 IL4Ra+ MSC 在免疫抑制中的作用。我们还将研究西地那非等 PDE5 抑制剂在消除 MSC 功能中的作用，并测试各种治疗条件，以最大限度地提高抗肿瘤免疫力。摘要：有效抗癌免疫疗法的一个主要障碍是产生具有临床意义的抗肿瘤反应的能力。为此，宿主必须能够克服限制有效免疫反应发展的内在抑制机制。其中一种机制是骨髓抑制细胞（MSC）的产生，其随着肿瘤负荷的增加而增加并抑制免疫反应。迄今为止，该领域的大部分工作都集中在它们在实体瘤中的作用。在这里，我们建议检查间充质干细胞在液体肿瘤（即淋巴瘤）小鼠模型中的作用。我们还将尝试确定骨髓移植如何影响间充质干细胞的功能和更新。最后，根据我们最近观察到这些药物可以有效抑制 MSC 功能，我们将尝试制定通过使用伟哥和相关药物来降低移植环境中 MSC 功能的策略。