Preclinical Development Selective Targeting of Interferon g to Stromal Fibroblasts and Pericytes as a Novel Therapeutic Approach to Inhibit Angiogenesis and Tumor Growth

New approaches to block the function of tumor stromal cells such as cancer-associated fibroblasts and pericytes is an emerging field in cancer therapeutics as these cells play a crucial role in promoting angiogenesis and tumor growth via paracrine signals. Because of immunomodulatory and other antitumor activities, IFNg , a pleiotropic cytokine, has been used as an anticancer agent in clinical trials. Unfortunately only modest beneficial effects, but severe side effects, were seen. In this study, we delivered IFNg to stromal fibroblasts and pericytes, considering its direct antifibrotic activity, using our platelet-derived growth factor-beta receptor (PDGFbR)-binding carrier (pPB-HSA), as these cells abundantly express PDGFbR. We chemically conjugated IFNg to pPB-HSA using a heterobifunctional PEG linker. In vitro in NIH3T3 fibroblasts, pPB-HSA-IFNg conjugate activated IFNg-signaling (pSTAT1a) and inhibited their activation and migration. Furthermore, pPB-HSA-IFNg inhibited fibroblasts-induced tube formation of H5V endothelial cells. In vivo in B16 tumor-bearing mice, pPB-HSA-IFNg rapidly accumulated in tumor stroma and pericytes and significantly inhibited the tumor growth while untargeted IFNg and pPB-HSA carrier were ineffective. These antitumor effects of pPB-HSA-IFNg were attributed to the inhibition of tumor vascularization, as shown with a-SMA and CD-31 staining. Moreover, pPB-HSA-IFNg induced MHC-II expression specifically in tumors compared with untargeted IFNg , indicating the specificity of this approach. This study thus shows the impact of drug targeting to tumor stromal cells in cancer therapy as well as provides new opportunities to use cytokines for therapeutic application.Mol Cancer Ther; 11(11);