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

基本信息

批准号：
8977537
负责人：
Piotr J. Kraj
金额：
$ 1.09万
依托单位：
OLD DOMINION UNIVERSITY
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：
2012-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8977537
关键词：
Modulation Bone Morphogenic Protein signaling

项目摘要

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.

描述（由适用提供）：了解免疫系统的功能对于开发新型癌症疗法至关重要。我们发现，由活化效应子和Foxp3+调节性CD4+ T细胞（TR）表达的骨形态形态蛋白受体1a（BMPR1A，ALK-3）调节了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，其中还包括TGF-和激活素。 BMP在胚胎发育，组织分化和稳态以及癌症的发育中起着至关重要的作用。事实证明，BMP和激活素与TGF-�协同调节胸腺T细胞的发育，保持TR细胞和外周耐受性，但其功能的精确机制尚不清楚。在T细胞中删除BMPR1A的小鼠（BMPR1AT-RICE）的TR细胞和T细胞比例降低了IFN-水平较高？当激活时，IL-4的水平低于BMPR1A充足的细胞。此外，B16黑色素瘤在BMPR1AT小鼠中的生长较小，肿瘤很少浸润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如何促进活化的常规CD4+和TR细胞中的分子信号传导来调节效应子功能和抑制器表型。将研究BMPR1A如何将TR细胞归巢为肿瘤的机制。最后，使用BMPR1A抑制剂，我们将测试如何在正常T细胞中阻断BMPR1A功能以增强抗肿瘤免疫激素。这将确定BMPR1A是否可以针对癌症设计新的免疫疗法。