Targeting all transforming growth factor-b isoforms with an Fc chimeric receptor impairs tumor growth and angiogenesis of oral squamous cell cancer

Abstract

Tumor progression is governed by various growth factors and cytokines in the tumor microenvironment (TME). Among these, transforming growth factor-b (TGF-b) is secreted by various cell types residing in the TME and promotes tumor progression by inducing the epithelial-to-mesenchymal transition (EMT) of cancer cells and tumor angiogenesis. TGF-b comprises three isoforms, TGF-b1, -b2, and -b3, and transduces intracellular signals via TGF-b type I receptor (TbRI) and TGF-b type II receptor (TbRII). For the purpose of designing ligand traps that reduce oncogenic signaling in the TME, chimeric proteins comprising the ligand-interacting ectodomains of receptors fused with the Fc portion of immunoglobulin are often used. For example, chimeric soluble TbRII (TbRII-Fc) has been developed as an effective therapeutic strategy for targeting TGF-b ligands, but several lines of evidence indicate that TbRII-Fc more effectively traps TGF-b1 and TGF-b3 than TGF-b2, whose expression is elevated in multiple cancer types. In the present study, we developed a chimeric TGF-b receptor containing both TbRI and TbRII (TbRI-TbRII-Fc) and found that TbRI-TbRII-Fc trapped all TGF-b isoforms, leading to inhibition of both the TGF-b signal and TGF-b-induced EMT of oral cancer cells, whereas TbRII-Fc failed to trap TGF-b2. Furthermore, we found that TbRI-TbRII-Fc suppresses tumor growth and angiogenesis more effectively than TbRII-Fc in a subcutaneous xenograft model of oral cancer cells with high TGF-b expression. These results suggest that TbRI-TbRII-Fc may be a promising tool for targeting all TGF-b isoforms in the TME.