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 NK cell activation through the recruitment of 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.

Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells

“…+ TILs from NSCLC samples activated with anti-CD3/anti-CD28 antibodies expressed significantly higher surface levels of CD25 ( Figure 3A), CD69 ( Figure 3B), and the newly identified activation marker Siglec-5 (Supplemental Figure 4C) compared with similarly actiby engaging inhibitory CD33rSiglecs, such as Siglec-7 and Siglec-9 (21)(22)(23)(24)(25)(26). Engagement of Siglec-7 and Siglec-9 inhibits NK cellmediated tumor cell killing in vitro (22,23).…”

Sialic Acids Sweeten a Tumor's Life

“…Siglecs are expressed on most cells of the immune system and can transmit immunosuppressive signals upon binding to sialic acid ligands. Increased expression of siglec ligands by tumor cells could thus contribute to tumor immune evasion (5)(6)(7).…”

Lectin Galactoside-binding Soluble 3 Binding Protein (LGALS3BP) Is a Tumor-associated Immunomodulatory Ligand for CD33-related Siglecs

“…However, recent experiments described a Siglec-9 high , CD56 dim population of NK cells that were higher in frequency in cancer patients (16) . LGALS3BP could, therefore, also modulate the antitumor NK cell response, as shown for artificial ligands in vitro (39). Because the activating Siglec-14 is a paired receptor with Siglec-5 that emerged because of pathogen-host interactions (13), the first two domains used in Siglec-Fc chimeras for our binding assays differ in only one amino acid and bind to the same set of sialic acid-dependent ligands (13).…”

“…LGALS3BP Inhibits Neutrophil-mediated Tumor Cell Killing-Recent experiments showed that sialylated tumor cells could inhibit innate immune cell activation and tumor cell killing in vitro and in vivo, in particular by neutrophils and NK cells (16,17,39). Therefore, we wanted to investigate the capability of LGALS3BP to inhibit immune cell activation, in particular neutrophil activation.…”