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

Abstract

Immunotherapy is becoming an increasingly attractive therapeutic alternative for conventional cancer therapy. In recent years Foxp3+ regulatory T-cells (TR) 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 TR cells led to enhanced antitumor immune response and better efficacy of cancer vaccines. We report that Bone Morphogenic Protein Receptor 1α (BMPR1α, Alk-3), is expressed by activated effector CD4+ and TR cells and modulates functions of both cell types. Bone Morphogenic Proteins (BMPs) belong to the transforming growth factor (TGF)-β family of cytokines that also include TGFβ 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 TGFβ to regulate thymic T-cell development, maintain TR cells and control peripheral tolerance. Inactivation of BMPR1α in T-cells results in impaired thymic and peripheral generation of TR cells. BMPR1α -deficient activated T-cells produced higher level of interferon (IFN)-γ than BMPR1α-sufficient T-cells. Moreover, transplanted B16 melanoma tumors grew smaller in mice lacking expression of BMPR1α in T-cells and tumors had few infiltrating TR cells and a higher proportion of CD8+ T-cells than wild-type mice.

Bone morphogenetic protein signaling regulates skin inflammation via modulating dendritic cell function

“…These mice exhibited lower levels of Treg cells; moreover, naive CD4 1 T cells lacking BMPR1a failed to efficiently convert into Treg cells when cultured with TGF-b1. 40 In addition, our data are in line with other previous observations in murine cells showing that BMP signaling affects IL-2 production and Treg-cell differentiation in vitro. 41 We not only demonstrated that BMP receptor signaling promotes human Treg-cell generation but also showed, to our knowledge for the first time, distinct and successive roles for BMP versus classical TGF-b1 signaling in human Treg-cell generation from naive CD4 1 T cells.…”

“…45 In support of our findings, BMP2 and BMP4 were also shown to promote Treg-cell generation when added in vitro to murine Treg-cell generation cultures. 15,40,41,46 To our knowledge, this study is the first to demonstrate that BMP signaling plays an important role in inflammatory Treg-cell accumulation during skin inflammation.…”

TGF-β–mediated enhancement of T H 17 cell generation is inhibited by bone morphogenetic protein receptor 1α signaling

“…Deletion of BMPR1 gene did not substantially affect survival and expansion of peripheral CD4 + T cells. Although wild-type and BMPR1 T− mice have similar proportions and absolute cell numbers in the thymus and peripheral organs, in the absence of BMPR1, T reg cells are reduced (26). In contrast to T cell-specific deletion of TGF-RII, which causes lymphoproliferation, multiorgan leukocyte infiltration, and early lethality in mice, loss of BMPR1 did not result in similar spontaneous autoimmune phenotype (7,8).…”

Myelination in Multiple Sclerosis Lesions Is Associated with Regulation of Bone Morphogenetic Protein 4 and Its Antagonist Noggin

“…BMPs play a role in a variety of biological processes and they are expressed in numerous cell types [19]. For example, BMPs play a role in the regulation of immune processes [20]. BMPs are secretory growth factors that form the largest subgroup of the transforming growth factor beta (TGF-beta) superfamily signal ligands [21].…”