title: The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors.
abstract: CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University Medical Center, Stanford, CA 94305, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Willingham
authors.forename: Jens-Peter
authors.initials: JP
authors.lastname: Volkmer
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gentles
authors.forename: Debashis
authors.initials: D
authors.lastname: Sahoo
authors.forename: Piero
authors.initials: P
authors.lastname: Dalerba
authors.forename: Siddhartha S
authors.initials: SS
authors.lastname: Mitra
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Humberto
authors.initials: H
authors.lastname: Contreras-Trujillo
authors.forename: Robin
authors.initials: R
authors.lastname: Martin
authors.forename: Justin D
authors.initials: JD
authors.lastname: Cohen
authors.forename: Patricia
authors.initials: P
authors.lastname: Lovelace
authors.forename: Ferenc A
authors.initials: FA
authors.lastname: Scheeren
authors.forename: Mark P
authors.initials: MP
authors.lastname: Chao
authors.forename: Kipp
authors.initials: K
authors.lastname: Weiskopf
authors.forename: Chad
authors.initials: C
authors.lastname: Tang
authors.forename: Anne Kathrin
authors.initials: AK
authors.lastname: Volkmer
authors.forename: Tejaswitha J
authors.initials: TJ
authors.lastname: Naik
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Storm
authors.forename: Adriane R
authors.initials: AR
authors.lastname: Mosley
authors.forename: Badreddin
authors.initials: B
authors.lastname: Edris
authors.forename: Seraina M
authors.initials: SM
authors.lastname: Schmid
authors.forename: Chris K
authors.initials: CK
authors.lastname: Sun
authors.forename: Mei-Sze
authors.initials: MS
authors.lastname: Chua
authors.forename: Oihana
authors.initials: O
authors.lastname: Murillo
authors.forename: Pradeep
authors.initials: P
authors.lastname: Rajendran
authors.forename: Adriel C
authors.initials: AC
authors.lastname: Cha
authors.forename: Robert K
authors.initials: RK
authors.lastname: Chin
authors.forename: Dongkyoon
authors.initials: D
authors.lastname: Kim
authors.forename: Maddalena
authors.initials: M
authors.lastname: Adorno
authors.forename: Tal
authors.initials: T
authors.lastname: Raveh
authors.forename: Diane
authors.initials: D
authors.lastname: Tseng
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Jaiswal
authors.forename: Per Øyvind
authors.initials: PØ
authors.lastname: Enger
authors.forename: Gary K
authors.initials: GK
authors.lastname: Steinberg
authors.forename: Gordon
authors.initials: G
authors.lastname: Li
authors.forename: Samuel K
authors.initials: SK
authors.lastname: So
authors.forename: Ravindra
authors.initials: R
authors.lastname: Majeti
authors.forename: Griffith R
authors.initials: GR
authors.lastname: Harsh
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
authors.forename: Nelson N H
authors.initials: NN
authors.lastname: Teng
authors.forename: John B
authors.initials: JB
authors.lastname: Sunwoo
authors.forename: Ash A
authors.initials: AA
authors.lastname: Alizadeh
authors.forename: Michael F
authors.initials: MF
authors.lastname: Clarke
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
mesh_terms: D000906:Antibodies / Q000276:immunology; D000943:Antigens, Differentiation / Q000378:metabolism*; D051928:CD47 Antigen / Q000235:genetics / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D010587:Phagocytosis / Q000276:immunology; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics*; D011971:Receptors, Immunologic / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D000906:Antibodies; D000943:Antigens, Differentiation; D051928:CD47 Antigen; D012333:RNA, Messenger; D011971:Receptors, Immunologic; C501920:SIRPA protein, human