Interaction of sialylated glycans with Siglec receptors on suppressive myeloid cells

In spite of the impressive advances in cancer immunotherapy that have entered the clinics, only a subset of patients benefits from current treatment strategies and many fail to achieve a durable response. Most treatment regimens are T cell-centric and neglect the role of the suppressive tumor microenvironment (TME) that drives various resistance mechanisms. Myeloid cells are the most abundant immune cells found in the TME and include immunosuppressive subsets such as myeloid-derived suppressor cells (MDSCs). In addition, overexpression of sialoglycans within the TME can drive tumor progression via various mechanisms. Hypersialylation can, for example, enhance immune evasion via interaction with sialic acid-binding immunoglobulin-like lectin (Siglec) receptors on tumor-infiltrating immune cells. Here, we tested the role of sialic acid on MDSCs and their interaction with Siglec receptors. We found that MDSCs derived from the blood of lung cancer patients and tumor- bearing mice strongly express inhibitory Siglec receptors. In murine cancer models of emergency myelopoiesis, Siglec-E knockout on myeloid cells resulted in prolonged survival and increased infiltration of activated T cells. Targeting suppressive myeloid cells by blocking Siglec receptors or desialylation led to a strong reduction of their suppressive potential. We further identified CCL2 as a mediator involved in T cell suppression upon the interaction of sialoglycans and Siglec receptors on MDSCs. Our results provide mechanistic insights into how sialylated glycans inhibit anti-cancer immunity by facilitating CCL2 expression. This interaction marks a new potential target to limit the suppressive capacity of the TME and induce anti-tumor response.