Sialofucosylation Enables Platelet Binding to Myeloma Cells via P-Selectin and Suppresses NK Cell-Mediated Cytotoxicity

SIMPLE SUMMARY: Platelet cloaking of tumor cells has been shown to play an important role in tumor metastasis and immune evasion. Multiple myeloma is a tumor of the plasma cells that colonizes different sites of the axial skeleton, including the skull. Herein, we show that specific carbohydrate structures present on the surface of multiple myeloma cells are essential in mediating direct interaction between the platelets and malignant plasma cells, which can be blocked by targeting P-selectin. Platelet binding to myeloma cells inhibits natural killer cell-mediated cytotoxicity, facilitating tumor immune evasion. We propose that platelets are important players in multiple myeloma dissemination, and targeting myeloma–platelet interactions may represent a novel strategy for myeloma treatment. ABSTRACT: Multiple myeloma (MM) is a plasma cell disorder that develops in the bone marrow (BM) and is characterized by uncontrolled proliferation and the ability to disseminate to different sites of the skeleton. Sialofucosylated structures, particularly Sialyl Lewis a/x (SLe(a/x)), facilitate the homing of MM cells into the BM, leading to resistance to bortezomib in vivo. Platelets have been shown to play an important role in tumor metastasis. Platelets can bind to the surface of cancer cells, forming a “cloak” that protects them from the shear stress of the bloodstream and natural killer (NK) cell-mediated cytotoxicity. In this study, we showed that the presence of SLe(a/x) induced a strong binding of MM cells to P-selectin, leading to specific and direct interactions with platelets, which could be inhibited by a P-selectin-blocking antibody. Importantly, platelets surrounded SLe(a/x)-enriched MM cells, protecting them from NK cell-mediated cytotoxicity. The interactions between the platelets and MM cells were also detected in BM samples obtained from MM patients. Platelet binding to SLe(a/x)-enriched MM cells was increased in patients with symptomatic disease and at relapse. These data suggest an important role of SLe(a/x) and platelets in MM disease progression and resistance to therapy.