MM is Multiple Myeloma (MM) is a malignancy of plasma cells that remains incurable despite many recent advances in treatment options. Aberrant hypersialylation is a feature of many cancers, including MM. Via pleiotropic mechanisms, which include engagement of inhibitory receptors on immune cells by sialylated Siglec ligands, hypersialylated MM cells can induce immune suppression within the bone marrow (BM) microenvironment and elevated expression of genes implicated in Siglec ligand synthesis are associated with inferior outcome, even with intensive Daratumumab based induction and transplant approaches. Recent evidence also suggests an important role for sialylation of stromal cells in contributing to this immune suppression. Together, hypersialylation of MM cells and BM stroma could be an important factor in resistance to treatment with T cell redirected therapies, such as bispecific antibodies. We aim to test this hypothesis by evaluating the in-vitro sensitivity of MM cells to killing by bispecific T cell engaging antibodies in the presence of treatments designed to selectively remove sialic acids from the surface of MM and/or BM stromal cells. This will include samples from patients who have progressed on treatment with these antibodies. We aim to further assess the translational relevance of our findings, including an analysis of transcriptomic data from the ongoing MajesTEC-4 study. In particular, we aim to assess the prognostic relevance of genes known to be involved in sialic acid biosynthesis and generation of Siglec ligands. Finally, as a pilot study we aim to explore the value of spatial multiplex imaging in bone marrows from MM patients treated with bispecific antibodies, focusing on interactions and identity of cell types expressing Siglec ligands and their receptors, respectively. Understanding how sialylation in the MM TME is regulated and functions to enhance immunosuppression could uncover novel immune checkpoints to reactivate T cell anti-tumor immunity.
