title: Therapeutic activity of high-dose intratumoral IFN-β requires direct effect on the tumor vasculature.
abstract: Endogenous type I IFN production after innate immune recognition of tumor cells is critical for generating natural adaptive immune responses against tumors in vivo. We recently have reported that targeting low doses of IFN-β to the tumor microenvironment using tumor-specific mAbs can facilitate antitumor immunity, which could be augmented further with PD-L1/PD-1 blockade. However, sustained high doses of type I IFNs in the tumor microenvironment, which are potently therapeutic alone, may function through distinct mechanisms. In the current report, we demonstrate that high-dose intratumoral type I IFNs indeed exerted a profound therapeutic effect in the murine B16 model, which unexpectedly did not increase T cell responses. Moreover, bone marrow chimeras revealed a role for type I IFN signaling on nonhematopoietic cells, and most of the therapeutic effect was retained in mice deficient in T, B, and NK cells. Rather, the tumor vasculature was ablated with high-dose intratumoral IFN-β, and conditional deletion of IFN-α/βR in Tie2-positive vascular endothelial cells eliminated most of the antitumor activity. Therefore, the major component of the antitumor activity of sustained high doses of type I IFNs occurs through a direct antiangiogenic effect. Our data help resolve conditions under which distinct antitumor mechanisms of type I IFNs are operational in vivo.
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637; and.
authors.forename: Robbert M
authors.initials: RM
authors.lastname: Spaapen
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637; and.
authors.forename: Michael Y K
authors.initials: MY
authors.lastname: Leung
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637; and.
authors.forename: Mercedes B
authors.initials: MB
authors.lastname: Fuertes
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Kline
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637; and.
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637; and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637; and.
authors.forename: Yang-Xin
authors.initials: YX
authors.lastname: Fu
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637; and.
authors.forename: Xixi
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637; and.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Cohen
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637; and Department of Medicine, University of Chicago, Chicago, IL 60637 tgajewsk@medicine.bsd.uchicago.edu.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001402:B-Lymphocytes / Q000276:immunology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D016899:Interferon-beta / Q000008:administration & dosage*; D007694:Killer Cells, Natural / Q000276:immunology; D008212:Lymphocyte Depletion; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D053633:Receptor, Interferon alpha-beta / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C508032:Ifnar1 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta