title: Immune cell inhibition by SLAMF7 is mediated by a mechanism requiring src kinases, CD45, and SHIP-1 that is defective in multiple myeloma cells.
abstract: Signaling lymphocytic activation molecule F7 (SLAMF7) is a receptor present on immune cells, including natural killer (NK) cells. It is also expressed on multiple myeloma (MM) cells. This led to development of an anti-SLAMF7 antibody, elotuzumab, showing efficacy against MM. SLAMF7 mediates activating or inhibitory effects in NK cells, depending on whether cells express or do not express the adaptor EAT-2. Since MM cells lack EAT-2, we elucidated the inhibitory effectors of SLAMF7 in EAT-2-negative NK cells and tested whether these effectors were triggered in MM cells. SLAMF7-mediated inhibition in NK cells lacking EAT-2 was mediated by SH2 domain-containing inositol phosphatase 1 (SHIP-1), which was recruited via tyrosine 261 of SLAMF7. Coupling of SLAMF7 to SHIP-1 required Src kinases, which phosphorylated SLAMF7. Although MM cells lack EAT-2, elotuzumab did not induce inhibitory signals in these cells. This was at least partly due to a lack of CD45, a phosphatase required for Src kinase activation. A defect in SLAMF7 function was also observed in CD45-deficient NK cells. Hence, SLAMF7-triggered inhibition is mediated by a mechanism involving Src kinases, CD45, and SHIP-1 that is defective in MM cells. This defect might explain why elotuzumab eliminates MM cells by an indirect mechanism involving the activation of NK cells.
authors.affiliation: Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, Québec, Canada Department of Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Huaijian
authors.initials: H
authors.lastname: Guo
authors.affiliation: Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, Québec, Canada Faculty of Medicine, University of Morelos, Cuernavaca, Mexico.
authors.forename: Mario-Ernesto
authors.initials: ME
authors.lastname: Cruz-Munoz
authors.affiliation: Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, Québec, Canada.
authors.forename: Ning
authors.initials: N
authors.lastname: Wu
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Robbins
authors.affiliation: Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, Québec, Canada Department of Medicine, McGill University, Montréal, Québec, Canada Department of Medicine, University of Montréal, Montréal, Québec, Canada veillea@ircm.qc.ca.
authors.forename: André
authors.initials: A
authors.lastname: Veillette
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D007694:Killer Cells, Natural / Q000166:cytology*; D017493:Leukocyte Common Antigens / Q000378:metabolism*; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000378:metabolism*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction; D000071176:Signaling Lymphocytic Activation Molecule Family; D014443:Tyrosine / Q000737:chemistry; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D011971:Receptors, Immunologic; C448987:SLAMF7 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family; C546027:elotuzumab; D014443:Tyrosine; D019061:src-Family Kinases; D010744:Phosphoric Monoester Hydrolases; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases