MYC-driven synthesis of Siglec ligands is a glycoimmune checkpoint

Abstract

The Siglecs (sialic acid-binding immunoglobulin-like lectins) are glycoimmune checkpoint receptors that suppress immune cell activation upon engagement of cognate sialoglycan ligands. The cellular drivers underlying Siglec ligand production on cancer cells are poorly understood. We find the MYC oncogene causally regulates Siglec ligand production to enable tumor immune evasion. A combination of glycomics and RNA-sequencing of mouse tumors revealed the MYC oncogene controls expression of the sialyltransferase St6galnac4 and induces a glycan known as disialyl-T. Using in vivo models and primary human leukemias, we find that disialyl-T functions as a “don’t eat me” signal by engaging macrophage Siglec-E in mice or the human ortholog Siglec-7, thereby preventing cancer cell clearance. Combined high expression of MYC and ST6GALNAC4 identifies patients with high-risk cancers and reduced tumor myeloid infiltration. MYC therefore regulates glycosylation to enable tumor immune evasion. We conclude that disialyl-T is a glycoimmune checkpoint ligand. Thus, disialyl-T is a candidate for antibody-based checkpoint blockade, and the disialyl-T synthase ST6GALNAC4 is a potential enzyme target for small molecule-mediated immune therapy.

Disruption of the sialic acid/Siglec-9 axis improves antibody-mediated neutrophil cytotoxicity towards tumor cells

“…In a fluorescence-based assay using chemically engineered glycans, sLewisA, sLewisX and sTn were identified as the most prominent glycans that bind Siglec-9. Binding of Siglec-9 to sLewisX has been previously described ( 67 ) and recently, sLewisA and sLewisX have been reported as MYC-driven ligands of Siglecs ( 68 ). The breast tumor cell lines used in our study express low levels of sLewisA/CA19-9 and high levels of sLewisX on the cell surface.…”

ST3Gal1 synthesis of Siglec ligands mediates anti-tumour immunity in prostate cancer

“…Previous studies have shown that Siglec-7 and Siglec-9 ligands are found on O-glycans (62,(67)(68)(69). Siglec-7 and -9 and their murine equivalent Siglec-E have been shown previously to be important glyco-immune checkpoints, directly promoting a protumour macrophage phenotype which can suppress cytotoxic CD8 + T cells (15,21,58).…”

“…Siglec-E is considered a Siglec-7 and Siglec-9 ortholog/paralog in mice (61). Siglec-E has been broadly described as a key glyco-immune checkpoint in multiple cancers and targeting of Siglec-E has been shown to repolarise immunosuppressive macrophages towards proinflammatory phenotype (15,61,62). We profiled expression of Siglec-E throughout the TIME in our syngeneic allograft model.…”

Antibody-lectin chimeras for glyco-immune checkpoint blockade

“…The same study noted that a single supplier offers 287 unique antibodies to tubulin and 269 unique antibodies to CD4, meaning that there are more antibodies to these two proteins available from a single supplier than all the commercially available anti-glycan antibodies combined. Further complicating monoclonal antibody development is the fact that many lectin receptors have multiple ligands that are expressed in the context of cancer 10,15,17,23,29 , and often the precise identities of their ligands are unknown. “Decoy receptor” molecules composed of a lectin glycan-binding domain fused to an antibody Fc domain address this complexity by retaining native glycan-binding specificities; however, their low binding affinities (typically with K D s in the μM to mM range 30 ) preclude their use as therapeutics.…”