The role of myeloid suppressor cells in tumor-specific tolerance

描述（由申请人提供）：越来越多的人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，这些途径对携带癌症的宿主的肿瘤抗原存在显著的障碍。其中，髓样抑制细胞（MSCs）与增加肿瘤负荷直接相关，并通过产生一氧化氮和精氨酸酶-1发挥其抑制作用。在这项提议中，我们寻求：1)在T细胞受体转基因模型中确定MSCs的产生与抗原特异性T细胞耐受的发展之间的关系，并特别关注MSCs与Tregs之间的相互关系。2)检查MSCs在血液系统恶性肿瘤进展中的作用。3)研究骨髓移植在MSC转换中的作用，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+ MSCs在免疫抑制中的作用。我们还将研究PDE5抑制剂如西地那非在消除间充质干细胞功能中的作用，并测试各种治疗条件，以最大限度地提高抗肿瘤免疫。摘要：有效的抗癌免疫治疗的一个主要障碍是能否产生临床意义上的抗肿瘤反应。要做到这一点，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（MSCs）的产生，这种细胞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肿瘤中的作用上。在这里，我们建议研究骨髓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转换。最后，我们将尝试制定策略，通过使用伟哥和相关药物，在移植环境中降低MSC功能，基于我们最近的观察，这些药物可以有效地抑制MSC功能。

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.