title: Anti-SIRPαantibodies as a potential new tool for cancer immunotherapy.
abstract: Tumor cells are thought to evade immune surveillance through interaction with immune cells. Much recent attention has focused on the modification of immune responses as a basis for new cancer treatments. SIRPα is an Ig superfamily protein that inhibits phagocytosis in macrophages upon interaction with its ligand CD47 expressed on the surface of target cells. Here, we show that SIRPα is highly expressed in human renal cell carcinoma and melanoma. Furthermore, an anti-SIRPα Ab that blocks the interaction with CD47 markedly suppressed tumor formation by renal cell carcinoma or melanoma cells in immunocompetent syngeneic mice. This inhibitory effect of the Ab appeared to be mediated by dual mechanisms: direct induction of Ab-dependent cellular phagocytosis of tumor cells by macrophages and blockade of CD47-SIRPα signaling that negatively regulates such phagocytosis. The antitumor effect of the Ab was greatly attenuated by selective depletion not only of macrophages but also of NK cells or CD8+T cells. In addition, the anti-SIRPα Ab also enhances the inhibitory effects of Abs against CD20 and programmed cell death 1 (PD-1) on tumor formation in mice injected with SIRPα-nonexpressing tumor cells. Anti-SIRPα Abs thus warrant further study as a potential new therapy for a broad range of cancers.
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology.|Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Yanagita
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Murata
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tanaka
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Sei-Ichiro
authors.initials: SI
authors.lastname: Motegi
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.|Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Arai
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology.
authors.forename: Edwin Widyanto
authors.initials: EW
authors.lastname: Daniwijaya
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hazama
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology.
authors.forename: Ken
authors.initials: K
authors.lastname: Washio
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology.
authors.forename: Takenori
authors.initials: T
authors.lastname: Kotani
authors.affiliation: Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Gunma, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohnishi
authors.affiliation: Department of Integrative Medical Biology, Section for Histology and Cell Biology, Umeå University, Umeå, Sweden.
authors.forename: Per-Arne
authors.initials: PA
authors.lastname: Oldenborg
authors.affiliation: Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Noel Verjan
authors.initials: NV
authors.lastname: Garcia
authors.affiliation: Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.|MediCity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyasaka
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ishikawa
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.|Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Yae
authors.initials: Y
authors.lastname: Kanai
authors.affiliation: Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Komori
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matozaki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D051928:CD47 Antigen / Q000187:drug effects / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000378:metabolism; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D010587:Phagocytosis / Q000187:drug effects; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D000943:Antigens, Differentiation; D051928:CD47 Antigen; C497894:CD47 protein, human; D011971:Receptors, Immunologic; C501920:SIRPA protein, human