MUC1 modulates the tumor immune microenvironment through the engagement of Siglec-9

Siglec-9 is a sialic acid binding lectin predominantly expressed on myeloid cells. Aberrant glycosylation occurs in essentially all types of cancers resulting in increased sialylation. Thus when MUC1 is expressed on cancer cells it is decorated by multiple short, sialylated O-linked glycans (MUC1-ST). Here we show that this cancer-specific MUC1 glycoform could, through the engagement of Siglec-9, educate myeloid cells to release factors associated with tumor microenvironment determination and disease progression. Moreover MUC1-ST induced macrophages to display a TAM-like phenotype with increased expression of PD-L1. MUC1-ST binding to Siglec-9 did not activate SHP-1/2 but surprisingly induced calcium flux leading to MEK-ERK activation. This work defines a critical role for aberrantly glycosylated MUC1 and identifies an activating pathway following Siglec-9 engagement.