Progression of melanoma is suppressed by targeting all transforming growth factor-β isoforms with an Fc chimeric receptor

Melanoma is an aggressive type of cancer originating from the skin that arises from neoplastic changes in melanocytes. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine and is known to contribute to melanoma progression by inducing the epithelial-mesenchymal transition (EMT) program and creating an environment that favors tumor progression. There are three TGF-β isoforms, TGF-β1, TGF-β2 and TGF-β3, all of which engage in pro-tumorigenic activities by activating SMAD signaling pathways. All TGF-β isoforms activate signaling pathways by binding to their TGF-β type I (TβRI) and type II (TβRII) receptors. Thus, effective targeting of all TGF-β isoforms is of great importance. In the present study, chimeric proteins comprising the extracellular domains of TβRI and/or TβRII fused with the Fc portion of human immunoglobulin (IgG) were validated in the melanoma context. The Fc chimeric receptor comprising both TβRI and TβRII (TβRI-TβRII-Fc) effectively trapped all TGF-β isoforms. Conversely, TβRII-Fc chimeric receptor, that comprises TβRII only, was able to interact with TGF-β1 and TGF-β3 isoforms, but not with TGF-β2, which is a poor prognostic factor for melanoma patients. Accordingly, it was revealed that TβRI-TβRII-Fc chimeric receptor suppressed the EMT program in melanoma cells in vitro induced by any of the three TGF-β isoforms, as revealed by decreased expression of mesenchymal markers. Conversely, TβRII-Fc chimeric receptor inhibited the EMT program induced by TGF-β1 and TGF-β3. In addition, it was established that tumor growth in subcutaneous mouse melanoma was inhibited by TβRI-TβRII-Fc chimeric receptor indicating that Fc chimeric receptor could be applied to modify the tumor microenvironment (TME) of melanoma. Therefore, designing of Fc chimeric receptors targeting TGF-β signals that affect various components of the TME may result in the development of effective anti-melanoma agents.