Modulation of Bone Morphogenic Protein signaling for cancer immunotherapy

点击翻译按钮获取中文摘要

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.