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新的癌症治疗方法至关重要。我们发现骨形态发生蛋白受体1a （BMPR1a, Alk-3）通过激活效应和Foxp3+调节性CD4+ T细胞（TR）表达，调节两种细胞类型的功能。骨形态发生蛋白（BMPs）属于TGF-¿细胞因子家族，该家族还包括TGF-¿和激活素。bmp在胚胎发育、组织分化、体内平衡和癌症发展中起着至关重要的作用。研究表明，bmp和激活素与TGF-¿协同调节胸腺T细胞发育，维持TR细胞和外周耐受性，但其功能的确切机制尚不清楚。在T细胞中缺失BMPR1a的小鼠（BMPR1aT-小鼠）TR细胞比例降低，T细胞产生更高水平的IFN-？激活后IL-4水平低于bmpr1a充足的细胞。此外，B16黑色素瘤肿瘤在BMPR1aT-小鼠中变小，肿瘤中浸润的TR细胞很少，表明BMPR1a控制TR细胞向肿瘤病变的迁移。本提案的目的是了解BMPR1a如何在活化的常规CD4+和TR细胞中参与分子信号传导，以调节效应功能和抑制表型。BMPR1a如何控制TR细胞归巢进入肿瘤的机制将被研究。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反应。这将确定BMPR1a是否可以用于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.