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

Oncol Rep. 2021 Sep;46(3):197. doi: 10.3892/or.2021.8148. Epub 2021 Jul 23.

Abstract

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.

Keywords: EMT; Fc chimeric receptor; TGF‑β; melanoma; tumor microenvironment.

Grant support

The present study was supported by a research program of the Japan Agency for Medical Research and Development (AMED) (grant no. 20cm0106253h0002 to TW). The present study was also supported in part by the Grant-in-Aid for Scientific Research (C) (grant nos. 17K11828 and 20K10111 to KAPI) and Grant-in-Aid for Early-Career Scientists (grant no. 19K19194 to TU) from the Japan Society for the Promotion of Science (JSPS).