Selective Targeting of Interferon γ 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, IFN gamma, 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 IFN gamma 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 IFN gamma to pPB-HSA using a heterobifunctional PEG linker. In vitro in NIH3T3 fibroblasts, pPB-HSA-IFN gamma conjugate activated IFN gamma-signaling (pSTAT1 alpha) and inhibited their activation and migration. Furthermore, pPB-HSA-IFN gamma inhibited fibroblasts-induced tube formation of H5V endothelial cells. In vivo in B16 tumor-bearing mice, pPB-HSA-IFN gamma rapidly accumulated in tumor stroma and pericytes and significantly inhibited the tumor growth while untargeted IFN gamma and pPB-HSA carrier were ineffective. These antitumor effects of pPB-HSA-IFN gamma were attributed to the inhibition of tumor vascularization, as shown with alpha-SMA and CD-31 staining. Moreover, pPB-HSA-IFN gamma induced MHC-II expression specifically in tumors compared with untargeted IFN gamma, 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); 2419-28. (C) 2012 AACR.