title: Glycocalyx engineering reveals a Siglec-based mechanism for NK cell immunoevasion.
abstract: The increase of cell surface sialic acid is a characteristic shared by many tumor types. A correlation between hypersialylation and immunoprotection has been observed, but few hypotheses have provided a mechanistic understanding of this immunosuppressive phenomenon. Here, we show that increasing sialylated glycans on cancer cells inhibits human natural killer (NK) cell activation through the recruitment of sialic acid-binding immunoglobulin-like lectin 7 (Siglec-7). Key to these findings was the use of glycopolymers end-functionalized with phospholipids, which enable the introduction of synthetically defined glycans onto cancer cell surfaces. Remodeling the sialylation status of cancer cells affected the susceptibility to NK cell cytotoxicity via Siglec-7 engagement in a variety of tumor types. These results support a model in which hypersialylation offers a selective advantage to tumor cells under pressure from NK immunosurveillance by increasing Siglec ligands. We also exploited this finding to protect allogeneic and xenogeneic primary cells from NK-mediated killing, suggesting the potential of Siglecs as therapeutic targets in cell transplant therapy.
authors.affiliation: 1] Department of Chemistry, University of California-Berkeley, Berkeley, California, USA. [2].
authors.forename: Jason E
authors.initials: JE
authors.lastname: Hudak
authors.affiliation: 1] Department of Chemistry, University of California-Berkeley, Berkeley, California, USA. [2].
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Canham
authors.affiliation: 1] Department of Chemistry, University of California-Berkeley, Berkeley, California, USA. [2] Molecular and Cell Biology, University of California-Berkeley, Berkeley, California, USA. [3] Howard Hughes Medical Institute, University of California-Berkeley, Berkeley, California, USA.
authors.forename: Carolyn R
authors.initials: CR
authors.lastname: Bertozzi
mesh_terms: D045744:Cell Line, Tumor; D019276:Glycocalyx / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion; D007694:Killer Cells, Natural / Q000276:immunology*; D063265:Sialic Acid Binding Immunoglobulin-like Lectins / Q000502:physiology*
chemical_list: D063265:Sialic Acid Binding Immunoglobulin-like Lectins