Natural Killer (NK) cells play a vital role in the immune response against multiple myeloma (MM). However, their cytotoxic function is suppressed by the immunosuppressive tumour microenvironment, including stromal cells. One particular mechanism involves excessive glycosylation of MM and stromal cells, which is shown to contribute to immune evasion, and is associated with poorer prognosis. Specifically, hypersialylation – the excess addition of sialic acids to glycoproteins and glycolipids on cell surfaces – alters immune cell responses and enhances metastasis. This project aims to investigate how tumour/inflammation induced hypersialylation of stromal cells suppresses NK cell function in MM. Using a co-culture system, stromal cells will be conditioned to express elevated levels of sialic acids. These sialylated stromal cells will then be co-cultured with NK cells to assess the impact on their cytotoxic activity against myeloma cells. The study will provide insights into sialylation-mediated immunosuppressive pathways in MM, paving the way for novel therapeutic strategies to restore NK cell function by targeting sialic acid-related mechanisms. Such interventions could significantly enhance MM treatment outcomes.
References:
Daly J, Sarkar S, Natoni A, Stark JC, Riley NM, Bertozzi CR, Carlsten M, O’Dwyer ME. Targeting hypersialylation in multiple myeloma represents a novel approach to enhance NK cell-mediated tumor responses. Blood Adv. 2022 Jun 14;6(11):3352-3366.
Egan H, Treacy O, Lynch K, Leonard NA, O’Malley G, Reidy E, O’Neill A, Corry SM, De Veirman K, Vanderkerken K, Egan LJ, Ritter T, Hogan AM, Redmond K, Peng L, Che J, Gatlin W, Jayaraman P, Sheehan M, Canney A, Hynes SO, Kerr EM, Dunne PD, O’Dwyer ME, Ryan AE. Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment. Cell Rep. 2023 May 30;42(5):112475.