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.

SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin

“…4c). These tyrosines couple SLAMF7 to effectors, including the SAP adaptor EAT-2 (refs 15–17, 25). The Y→ F mutations had no impact on phagocytosis (Fig.…”

“…Here we show that macrophages selectively phagocytosed haematopoietic tumour cells in response to SIRP α –CD47 checkpoint blockade, in an FcR-independent manner. Phagocytosis was mediated by the homotypic, haematopoietic cell-specific receptor SLAMF7 (refs 15–17, 24, 25). It also required expression of integrin Mac-1, and of ITAM-containing subunits FcR γ and DAP12 (refs 21, 22).…”

PD-1 blockade enhances elotuzumab efficacy in mouse tumor models

“…Myeloma cells do not express EWS-Fl1-activated transcript-2 (or CD45, a phosphatase also required for SLAMF7 signaling), which may explain why elotuzumab does not directly induce MM cell apoptosis. 30 The activity of tumor-targeted mAbs can be improved with mAbs that modulate adaptive immune system responses. 12,31 Programmed death receptor-1 (PD-1) is an inhibitory receptor expressed on activated T cells as well as on NK cells and other immune cells.…”

Elotuzumab in combination with thalidomide and low‐dose dexamethasone: a phase 2 single‐arm safety study in patients with relapsed/refractory multiple myeloma

“…Binding to SLAMF7 directly activates natural killer cells (Collins et al, 2013) but not myeloma cells (Guo et al, 2015). Elotuzumab works via a dual mechanism of action, both by directly activating natural killer cells and through antibody-dependent cell-mediated cytotoxicity, to cause targeted myeloma cell death (Collins et al, 2013;Guo et al, 2015).…”

“…Elotuzumab is a first-in-class humanized IgG1 immunostimulatory monoclonal antibody that targets signalling lymphocytic activation molecule family member 7 (SLAMF7), a glycoprotein found to be expressed on natural killer cells, natural killer-like T cells, CD8-positive T cells, mature dendritic cells and activated B cells, is highly expressed on myeloma cells (>95%), but is not found on most normal tissues (Bouchon et al, 2001;Hsi et al, 2008). Binding to SLAMF7 directly activates natural killer cells (Collins et al, 2013) but not myeloma cells (Guo et al, 2015). Elotuzumab works via a dual mechanism of action, both by directly activating natural killer cells and through antibody-dependent cell-mediated cytotoxicity, to cause targeted myeloma cell death (Collins et al, 2013;Guo et al, 2015).…”