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

Shingo Kodama, Katarzyna Α Podyma-Inoue, Toshihiro Uchihashi, Kyoko Kurioka, Hitomi Takahashi, Akinari Sugauchi, Kazuki Takahashi, Toshihiro Inubushi, Mikihiko Kogo, Susumu Tanaka, Tetsuro Watabe

Oncology reports 2021 Sep

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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 immu noglobulin (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.

Citation

Shingo Kodama, Katarzyna Α Podyma-Inoue, Toshihiro Uchihashi, Kyoko Kurioka, Hitomi Takahashi, Akinari Sugauchi, Kazuki Takahashi, Toshihiro Inubushi, Mikihiko Kogo, Susumu Tanaka, Tetsuro Watabe. Progression of melanoma is suppressed by targeting all transforming growth factor‑β isoforms with an Fc chimeric receptor. Oncology reports. 2021 Sep;46(3)