Progression of melanoma is suppressed by targeting all transforming growth factor­ß isoforms with an Fc chimeric receptor.

ABSTRACT

Melanoma is an aggressive type of cancer originating from the skin that arises from neoplastic changes in melanocytes. Transforming growth factor­ß (TGF­ß) is a pleiotropic cytokine and is known to contribute to melanoma progression by inducing the epithelial­mesenchymal transition (EMT) program and creating an environment that favors tumor progression. There are three TGF­ß isoforms, TGF­ß1, TGF­ß2 and TGF­ß3, all of which engage in pro­tumorigenic activities by activating SMAD signaling pathways. All TGF­ß isoforms activate signaling pathways by binding to their TGF­ß type I (TßRI) and type II (TßRII) receptors. Thus, effective targeting of all TGF­ß isoforms is of great importance. In the present study, chimeric proteins comprising the extracellular domains of TßRI and/or TßRII fused with the Fc portion of human immunoglobulin (IgG) were validated in the melanoma context. The Fc chimeric receptor comprising both TßRI and TßRII (TßRI­TßRII­Fc) effectively trapped all TGF­ß isoforms. Conversely, TßRII­Fc chimeric receptor, that comprises TßRII only, was able to interact with TGF­ß1 and TGF­ß3 isoforms, but not with TGF­ß2, which is a poor prognostic factor for melanoma patients. Accordingly, it was revealed that TßRI­TßRII­Fc chimeric receptor suppressed the EMT program in melanoma cells in vitro induced by any of the three TGF­ß isoforms, as revealed by decreased expression of mesenchymal markers. Conversely, TßRII­Fc chimeric receptor inhibited the EMT program induced by TGF­ß1 and TGF­ß3. In addition, it was established that tumor growth in subcutaneous mouse melanoma was inhibited by TßRI­TßRII­Fc 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 TGF­ß signals that affect various components of the TME may result in the development of effective anti­melanoma agents.