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.

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ACKNOWLEDGMENTS

This work was supported by grants from the Canadian Institute of Health Research, the Canadian Cancer Society Research Institute, and Bristol-Myers Squibb (BMS) to A.V. H.G. held an Alma Mater Fellowship from McGill University and a Joseph-Paulin doctoral scholarship from IRCM. M.-E.C.-M. held fellowships from the Terry Fox Foundation and Cancer Research Society Inc., and N.W. holds a fellowship from the Fonds de Recherche du Québec—Santé. M.R. is an employee of BMS. A.V. holds the Canada Research Chair in Immune Cell Signaling.

A.V. served on the Scientific Advisory Board for elotuzumab at BMS.