Modulation of Bone Morphogenic Protein signaling for cancer immunotherapy

癌症免疫治疗中骨形态发生蛋白信号传导的调节

• 批准号: 8228616
• 负责人: Piotr J. Kraj
• 金额: $ 22.45万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8228616
• 关键词: Activins; Affect; Attenuated; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Development; Embryonic Development; Family; Goals; Homeostasis; Homing; Immune response; Immune system; Immunotherapy; Interferons; Interleukin-4; Lead; Lesion; Leucocytic infiltrate; Malignant Neoplasms; Mediating; Molecular; Mus; Pathway interactions; Phenotype; Play; Production; Research; Role; Signal Pathway; Signal Transduction; T-Cell Development; T-Lymphocyte; Testing; Tissue Differentiation; bone morphogenic protein; cancer immunotherapy; cancer therapy; cell type; cytokine; cytotoxic; design; inhibitor/antagonist; insight; melanoma; migration; novel; peripheral tolerance; receptor; research study; therapeutic target; trafficking; tumor; tumor growth

DESCRIPTION (provided by applicant): Understanding the functions of the immune system is critical for the development of novel therapies for cancer. We have found that Bone Morphogenic Protein Receptor 1a (BMPR1a, Alk-3), expressed by activated effector and Foxp3+ regulatory CD4+ T cells (TR), modulates the functions of both cell types. Bone Morphogenic Proteins (BMPs) belong to TGF-¿ family of cytokines that also includes TGF-¿ and activins. BMPs play crucial roles in embryonic development, tissue differentiation and homeostasis and development of cancer. It was demonstrated that BMPs and activins synergize with TGF-¿ to regulate thymic T cell development, maintain TR cells and peripheral tolerance but the precise mechanism of their function is not known. Mice where BMPR1a is deleted in T cells (BMPR1aT- mice) had a decreased proportion of TR cells and T cells produced higher level of IFN-? and lower level of IL-4 than BMPR1a-sufficient cells when activated. Moreover, B16 melanoma tumors grew smaller in BMPR1aT- mice and tumors had very few infiltrating TR cells suggesting that BMPR1a controls migration of TR cells into tumor lesions. The goal of this proposal is to understand the how BMPR1a contributes to molecular signaling in activated conventional CD4+ and TR cells to regulate effector function and suppressor phenotype. The mechanism how BMPR1a controls TR cell homing into tumors will be investigated. Finally, using BMPR1a inhibitors, we will test how BMPR1a function can be blocked in normal T cells to augment anti-tumor immune response. This will establish if BMPR1a can be targeted to design new immunotherapies for cancer. PUBLIC HEALTH RELEVANCE: The proposed research will study the cause of slower tumor growth in mice where T cells are not expressing Bone Morphogenic Protein Receptor1a. We will investigate how BMPR1a can be targeted to augment immune response in cancer. This will lead to the design of new forms of therapy.

描述（由申请人提供）：了解免疫系统的功能对于开发新的癌症疗法至关重要。我们发现骨形态发生蛋白受体 1a（BMPR1a，Alk-3）由激活的效应器和 Foxp3+ 调节性 CD4+ 表达。 T 细胞 (TR) 调节两种细胞类型的功能，骨形态发生蛋白 (BMP) 属于 TGF-¿细胞因子家族，还包括 TGF-¿ BMP 和激活素在胚胎发育、组织分化和体内平衡以及癌症的发展中发挥着重要作用。调节胸腺T细胞发育，维持TR细胞和外周耐受，但其功能的确切机制尚不清楚，T细胞中BMPR1a缺失的小鼠（BMPR1aT-小鼠）的TR细胞比例下降，T细胞产生更高水平。与BMPR1a充足的细胞相比，激活时，B16黑色素瘤的IFN-α和IL-4水平较低，而且BMPR1aT-小鼠中的B16黑色素瘤肿瘤变小，并且肿瘤具有很少的浸润TR。细胞表明 BMPR1a 控制 TR 细胞迁移到肿瘤病变中，该提案的目的是了解 BMPR1a 如何促进激活的常规 CD4+ 和 TR 细胞中的分子信号传导，从而调节效应功能和抑制表型。最后，我们将使用 BMPR1a 抑制剂来测试如何在正常 T 细胞中阻断 BMPR1a 功能以增强抗肿瘤免疫反应。 BMPR1a 可以靶向设计新的癌症免疫疗法。 公共健康相关性：拟议的研究将研究 T 细胞不表达骨形态发生蛋白受体 1a 的小鼠肿瘤生长缓慢的原因，我们将研究如何靶向 BMPR1a 来增强癌症的免疫反应。新的治疗形式。