Targeting hypersialylation in multiple myeloma represents a novel approach to enhance NK cell-mediated tumor responses

Abnormal glycosylation is a hallmark of cancer, and the hypersialylated tumor cell surface facilitates abnormal cell trafficking and drug resistance in several malignancies, including multiple myeloma (MM). Furthermore, hypersialylation has also been implicated in facilitating evasion of natural killer (NK) cell-mediated immunosurveillance but not in MM to date. In this study, we explore the role of hypersialylation in promoting escape from NK cells. We document strong expression of sialic acid-derived ligands for Siglec-7 (Siglec-7L) on primary MM cells and MM cell lines, highlighting the possibility of Siglec-7/Siglec-7L interactions in the tumor microenvironment. Interactomics experiments in MM cell lysates revealed PSGL-1 as the predominant Siglec-7L in MM. We show that desialylation, using both a sialidase and sialyltransferase inhibitor (SIA), strongly enhances NK cell-mediated cytotoxicity against MM cells. Furthermore, MM cell desialylation results in increased detection of CD38, a well-validated target in MM. Desialylation enhanced NK cell cytotoxicity against CD38(+) MM cells after treatment with the anti-CD38 monoclonal antibody daratumumab. Additionally, we show that MM cells with low CD38 expression can be treated with all trans-retinoic acid (ATRA), SIA and daratumumab to elicit a potent NK cell cytotoxic response. Finally, we demonstrate that Siglec-7(KO) potentiates NK cell cytotoxicity against Siglec-7L(+) MM cells. Taken together, our work shows that desialylation of MM cells is a promising novel approach to enhance NK cell efficacy against MM, which can be combined with frontline therapies to elicit a potent anti-MM response.