Modulation of bone morphogenic protein signaling in T-cells for cancer immunotherapy

Immunotherapy is becoming an increasingly attractive therapeutic alternative for conventional cancer therapy. In recent years Foxp3(+) regulatory T-cells (T-R) were identified as the major obstacle to effective cancer immunotherapy. The abundance of these cells in peripheral blood is increased in patients with multiple types of cancer and their prevalence among tumor-infiltrating lymphocytes correlated with poor clinical prognosis. In contrast, removal or inactivation of T-R cells led to enhanced anti-tumor immune response and better efficacy of cancer vaccines. This study reports that Bone Morphogenic Protein Receptor 1 alpha (BMPR1 alpha, Alk-3) is expressed by activated effector CD4(+) and T-R cells and modulates functions of both cell types. Bone Morphogenic Proteins (BMPs) belong to the transforming growth factor (TGF)-beta family of cytokines that also include TGF beta 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 beta to regulate thymic T-cell development, maintain T-R cells, and control peripheral tolerance. Inactivation of BMPR1 alpha in T-cells results in impaired thymic and peripheral generation of T-R cells. BMPR1 alpha-deficient activated T-cells produced a higher level of interferon (IFN)-gamma than BMPR1 alpha-sufficient T-cells. Moreover, transplanted B16 melanoma tumors grew smaller in mice lacking expression of BMPR1 alpha in T-cells and tumors had few infiltrating T-R cells and a higher proportion of CD8(+) T-cells than wild-type mice.