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

Abstract

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.

Interferon gamma peptidomimetic targeted to interstitial myofibroblasts attenuates renal fibrosis after unilateral ureteral obstruction in mice

“…To do so, pegylated full length IFNγ was conjugated to PDGFβR-recognizing peptide (PPB) [18] and by using this conjugate ( i.e. PPB-PEG-IFNγ) we were able to demonstrate anti-fibrotic effects in the CCl 4 -induced liver fibrosis mouse model [19] and anti-tumorigenic effects by targeting stromal cells in the B16 melanoma tumor mouse model [20]. Recently we used the same targeting approach as proof of concept in the mouse unilateral ureteral obstruction (UUO) model of renal fibrosis in which anti-fibrotic effects of the PPB-PEG-IFNγ conjugate were demonstrated [12].…”

Selective delivery of IFN‐γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis

“…Mesenchymal-derived cells including fibroblasts and pericytes constitutively express platelet-derived growth factor receptor b (PDGFRb) at a low level at physiologic conditions, whereas tissue injury is accompanied by increased expression of this receptor (24)(25)(26)(27)(28). An attractive approach for myofibroblast-specific delivery of IFN-g could therefore be based on the recognition of PDGFRb, which can be achieved by the use of a PDGFRb-recognizing cyclic peptide (PPB) (29)(30)(31). This carrier increases the half-life of drugs and also imparts receptor specificity by binding specifically to PDGFRb and, therefore, can be used for drug targeting to activated fibroblasts.…”

Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope

“…2,5,6,38 Although it is clear that most dermal fibroblast do not represent a fully accurate model of cancer-associated stromal cells found in vivo, following in vitro culture, our fibroblasts exhibited phosphorylated Erk and expressed a-SMA and platelet-derived growth factor receptor a, important markers of CAF-like stromal cells (data not shown). Therefore, we used these fibroblasts as a model of a-SMAeexpressing stromal cells and examined whether blocking the HU177 epitope could alter growth factoreinduced migration.…”