Galectin-9 as a glycan-modulating adjuvant to enhance Elotuzumab-mediated immunotherapy in multiple myeloma

Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal expansion of malignant antibody-producing plasma cells within the bone marrow. Despite advances in therapeutic strategies, MM remains incurable, emphasizing the need for innovative approaches to augment current immunotherapies. The surface glycan repertoire or glycome profile of myeloma cells plays a pivotal role in modulating host-tumor immune interactions, influencing both immune recognition and therapeutic responsiveness. Galectin-9 (Gal-9), a beta-galactoside-binding lectin, has emerged as a key regulator of immune and tumor cell signaling through its interaction with specific glycan structures. Recent findings from our laboratory revealed a strong binding affinity of Gal-9 for B cell surface glycans, resulting in the upregulation of signaling lymphocytic activation molecule F7 (SLAMF7), a critical immunoregulatory receptor expressed on malignant plasma cells and a validated therapeutic target of the monoclonal antibody Elotuzumab. In this study, we investigated whether Gal-9 treatment enhances Elotuzumab efficacy by modulating SLAMF7 expression and immune responsiveness in MM cells. Using flow cytometry, we quantified Gal-9 binding and SLAMF7 surface expression across B-lymphoblast models and primary MM bone marrow samples. Gal-9 exposure significantly increased SLAMF7 expression (~3-fold) compared to untreated controls. Furthermore, Gal-9-primed MM cells exhibited augmented antibody-dependent cellular cytotoxicity (ADCC) when co-cultured with natural killer (NK) cells in the presence of anti-SLAMF7 antibody Elotuzumab, suggesting (~2.5-fold) functional enhancement of immune-mediated cytotoxicity. All methods were conducted at least 3 times and analyzed for statistical significance using Student's t-test (*p≤0.05, **p≤0.01, *** p≤0.001). Collectively, these findings highlight Gal-9 as a promising combinatorial agent capable of enhancing SLAMF7 expression and amplifying Elotuzumab-induced cytotoxicity in MM. This study underscores the therapeutic potential of integrating glycan-targeting strategies with existing monoclonal antibody-based regimens to improve treatment efficacy and patient outcomes in multiple myeloma.