New manuscript accepted in Nature Immunology
MUC1 modulates the tumor immune microenvironment through the engagement of Siglec-9
Beatson R, Tajadura-Ortega V, Achkova D, Picco G, Tsourouktsoglou TD, Klausing S, Hillier M, Maher J, Noll T, Crocker PR, Taylor-Papadimitriou J and Burchell JM
Nature Immunology, doi:10.1038/ni.3552
The tumor microenvironment is populated by host cells educated to support growth, metastasis and promote an immunosuppressive environment. Siglec-9 is a sialic acid binding lectin predominantly expressed on myeloid cells able to negatively regulate immune and inflammatory responses through its ITIM motif. Aberrant, truncated, glycosylation occurs in essentially all types of cancers and often results in increased sialylation. Thus when the mucin MUC1 is expressed by cancer cells, it carries multiple short, sialylated O-linked glycans (MUC1-ST). Through the engagement of Siglec-9, we show that MUC1-ST can educate myeloid cells to release factors associated with microenvironment determination and disease progression, and to induce tumor-associated macrophages (TAMs), which show increased expression of PD-1L. We show that MUC1-ST binding to Siglec-9 does not activate SHP1/2 but surprisingly induces calcium flux leading to MEK/ERK activation. This work sheds light on the critical role of aberrantly glycosylated MUC1 in immune suppression and identifies a novel, activating pathway following Siglec-9 engagement.