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

• 批准号: 8121421
• 负责人: Ivan M. Borrello
• 金额: $ 30.23万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/8121421
• 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; IL2RA gene; 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; Regulatory T-Lymphocyte; Role; Solid Neoplasm; Suppressor-Effector T-Lymphocytes; T cell anergy; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Transgenic Model; Transplantation; Tumor Antigens; Tumor Burden; Tumor Immunity; Vaccination; Viagra; Work; abstracting; advanced disease; arginase; base; cancer immunotherapy; inhibitor/antagonist; mouse model; response; sildenafil; tumor; tumor progression

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）：越来越多地认识到有效免疫疗法的局限性。具体而言，已经确定了许多调节/抑制途径，这些途径呈现出癌症宿主中肿瘤抗原的明显障碍。其中，髓样抑制细胞（MSC）与增加肿瘤负担直接相关，并通过产生一氧化氮和精氨酸酶-1发挥其抑制作用。在此提案中，我们寻求：1）确定MSC的产生与T细胞受体转基因模型中抗原特异性T细胞耐受性之间的关系，并特别注意对MSC和Tregs之间的关系相互关系。 2）检查MSC在血液学恶性肿瘤中肿瘤进展中的作用。 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。具体而言，我们将研究利用lysmcre IL4RA+ Flox小鼠在免疫抑制中的IL4RA+ MSC的作用。我们还将研究诸如西地那非等PDE5抑制剂在废除MSC功能和测试各种治疗条件方面的作用，以最大程度地提高抗肿瘤免疫力。摘要摘要：有效抗癌免疫疗法的主要障碍是具有临床上有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。这样的机制是产生髓样抑制细胞（MSC），随着肿瘤负担的增加并抑制免疫反应能力。迄今为止，该领域的大多数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MSC在液体肿瘤的小鼠模型中的作用，即淋巴瘤。我们还将尝试确定骨髓移植对MSC功能和周转的影响。最后，我们将尝试通过使用伟哥和相关药物来制定策略来降低移植设置中的MSC功能，并基于我们最近的观察结果，即这些药物可以有效抑制MSC功能。

项目成果

Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function.

• DOI: 10.1084/jem.20061104
• 发表时间: 2006-11-27
• 期刊: The Journal of experimental medicine
• 作者: Serafini P;Meckel K;Kelso M;Noonan K;Califano J;Koch W;Dolcetti L;Bronte V;Borrello I
• 通讯作者: Borrello I

Targeting immune suppression with PDE5 inhibition in end-stage multiple myeloma.

• DOI: 10.1158/2326-6066.cir-13-0213
• 发表时间: 2014-08
• 期刊: Cancer immunology research
• 影响因子: 10.1
• 作者: Noonan KA;Ghosh N;Rudraraju L;Bui M;Borrello I
• 通讯作者: Borrello I

Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells.

• DOI: 10.1158/0008-5472.can-07-6621
• 发表时间: 2008-07-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Serafini P;Mgebroff S;Noonan K;Borrello I
• 通讯作者: Borrello I