title: 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, IFNγ, 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 IFNγ to stromal fibroblasts and pericytes, considering its direct antifibrotic activity, using our platelet-derived growth factor-beta receptor (PDGFβR)-binding carrier (pPB-HSA), as these cells abundantly express PDGFβR. We chemically conjugated IFNγ to pPB-HSA using a heterobifunctional PEG linker. In vitro in NIH3T3 fibroblasts, pPB-HSA-IFNγ conjugate activated IFNγ-signaling (pSTAT1α) and inhibited their activation and migration. Furthermore, pPB-HSA-IFNγ inhibited fibroblasts-induced tube formation of H5V endothelial cells. In vivo in B16 tumor-bearing mice, pPB-HSA-IFNγ rapidly accumulated in tumor stroma and pericytes and significantly inhibited the tumor growth while untargeted IFNγ and pPB-HSA carrier were ineffective. These antitumor effects of pPB-HSA-IFNγ were attributed to the inhibition of tumor vascularization, as shown with α-SMA and CD-31 staining. Moreover, pPB-HSA-IFNγ induced MHC-II expression specifically in tumors compared with untargeted IFNγ, 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.
authors.affiliation: Department of Targeted Therapeutics, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Bansal
authors.forename: Tushar
authors.initials: T
authors.lastname: Tomar
authors.forename: Arne
authors.initials: A
authors.lastname: Ostman
authors.forename: Klaas
authors.initials: K
authors.lastname: Poelstra
authors.forename: Jai
authors.initials: J
authors.lastname: Prakash
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010456:Peptides, Cyclic / Q000378:metabolism; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D017471:Receptors, Interferon / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D040521:Subcutaneous Tissue / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: C490116:Ifngr2 protein, mouse; D018796:Immunoconjugates; D010456:Peptides, Cyclic; D017471:Receptors, Interferon; D012709:Serum Albumin; D007371:Interferon-gamma; D020797:Receptor, Platelet-Derived Growth Factor beta