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-beta (TGF-beta) 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-beta isoforms, TGF-beta 1, TGF-beta 2 and TGF-beta 3, all of which engage in pro-tumorigenic activities by activating SMAD signaling pathways. All TGF-beta isoforms activate signaling pathways by binding to their TGF-beta type I (T beta RI) and type II (T beta RII) receptors. Thus, effective targeting of all TGF-beta isoforms is of great importance. In the present study, chimeric proteins comprising the extracellular domains of T beta RI and/or T beta RII fused with the Fc portion of human immunoglobulin (IgG) were validated in the melanoma context. The Fc chimeric receptor comprising both T beta RI and T beta RII (T beta RI-T beta RII-Fc) effectively trapped all TGF-beta isoforms. Conversely, T beta RII-Fc chimeric receptor, that comprises T beta RII only, was able to interact with TGF-beta 1 and TGF-beta 3 isoforms, but not with TGF-beta 2, which is a poor prognostic factor for melanoma patients. Accordingly, it was revealed that T beta RI-T beta RII-Fc chimeric receptor suppressed the EMT program in melanoma cells in vitro induced by any of the three TGF-beta isoforms, as revealed by decreased expression of mesenchymal markers. Conversely, T beta RII-Fc chimeric receptor inhibited the EMT program induced by TGF-beta 1 and TGF-beta 3. In addition, it was established that tumor growth in subcutaneous mouse melanoma was inhibited by T beta RI-T beta RII-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-beta signals that affect various components of the TME may result in the development of effective anti-melanoma agents.