Modulation of Bone Morphogenic Protein signaling for cancer immunotherapy

描述(由申请人提供)：了解免疫系统的功能对于开发癌症的新疗法至关重要。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+调节性的CD4+T细胞表达，对这两种细胞的功能都有调节作用。骨形态发生蛋白(BMP)属于转化生长因子-�家族，也包括转化生长因子-�和激活素。BMPS在胚胎发育、组织分化、动态平衡和肿瘤的发生发展中起着重要作用。研究表明，BMPs和激活素与转化生长因子-�协同调节胸腺T细胞发育，维持胸腺T细胞和外周免疫耐受，但其确切作用机制尚不清楚。T细胞中BMPR1a缺失的小鼠(BMPR1aT小鼠)的tr细胞比例降低，T细胞产生更高水平的干扰素？激活时IL-4水平低于BMPR1A充足的细胞。此外，在BMPR1aT-小鼠中，B16黑色素瘤肿瘤变得更小，肿瘤中几乎没有浸润性的TR细胞，这表明BMPR1A控制了TR细胞向肿瘤病变的迁移。该建议的目的是了解BMPR1A如何在激活的常规CD4+和TR细胞中参与分子信号转导，以调节效应器功能和抑制表型。BMPR1A如何控制TR细胞归巢到肿瘤的机制将被研究。最后，使用BMPR1A抑制剂，我们将测试BMPR1A功能如何在正常T细胞中被阻断，以增强抗肿瘤免疫反应。这将确定BMPR1A是否可以有针对性地设计新的癌症免疫疗法。

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.