title: Disruption of SIRPα signaling in macrophages eliminates human acute myeloid leukemia stem cells in xenografts.
abstract: Although tumor surveillance by T and B lymphocytes is well studied, the role of innate immune cells, in particular macrophages, is less clear. Moreover, the existence of subclonal genetic and functional diversity in some human cancers such as leukemia underscores the importance of defining tumor surveillance mechanisms that effectively target the disease-sustaining cancer stem cells in addition to bulk cells. In this study, we report that leukemia stem cell function in xenotransplant models of acute myeloid leukemia (AML) depends on SIRPα-mediated inhibition of macrophages through engagement with its ligand CD47. We generated mice expressing SIRPα variants with differential ability to bind human CD47 and demonstrated that macrophage-mediated phagocytosis and clearance of AML stem cells depend on absent SIRPα signaling. We obtained independent confirmation of the genetic restriction observed in our mouse models by using SIRPα-Fc fusion protein to disrupt SIRPα-CD47 engagement. Treatment with SIRPα-Fc enhanced phagocytosis of AML cells by both mouse and human macrophages and impaired leukemic engraftment in mice. Importantly, SIRPα-Fc treatment did not significantly enhance phagocytosis of normal hematopoietic targets. These findings support the development of therapeutics that antagonize SIRPα signaling to enhance macrophage-mediated elimination of AML.
authors.affiliation: The Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Alexandre P A
authors.initials: AP
authors.lastname: Theocharides
authors.forename: Liqing
authors.initials: L
authors.lastname: Jin
authors.forename: Po-Yan
authors.initials: PY
authors.lastname: Cheng
authors.forename: Tatiana K
authors.initials: TK
authors.lastname: Prasolava
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Malko
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Ho
authors.forename: Armando G
authors.initials: AG
authors.lastname: Poeppl
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.forename: Jayne S
authors.initials: JS
authors.lastname: Danska
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
authors.forename: Jean C Y
authors.initials: JC
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism*; D051928:CD47 Antigen / Q000378:metabolism; D005260:Female; D006085:Graft Survival / Q000276:immunology; D006410:Hematopoiesis / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000378:metabolism*; D008212:Lymphocyte Depletion; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010587:Phagocytosis / Q000276:immunology; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D055815:Young Adult
chemical_list: D000943:Antigens, Differentiation; D051928:CD47 Antigen; D011971:Receptors, Immunologic; C501920:SIRPA protein, human