Progression Of Melanoma Is Suppressed By Targeting All Transforming Growth Factor-Beta 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.