Deglycosylation of SLAMF7 in breast cancers enhances phagocytosis

by Selleckchem | Oct 24 2023

N-linked glycosylation of proteins is one of the post-translational modifications (PTMs) that shield tumor antigens from immune attack. Signaling lymphocytic activation molecule family 7 (SLAMF7) suppresses cancer cell phagocytosis and is an ideal target under clinical development. PTM of SLAMF7, however, remains less understood. In this study, we investigated the role of N-glycans on SLAMF7 in breast cancer progression. We identified seven N-linked glycosylation motifs on SLAMF7, which are majorly occupied by complex structures. Evolutionally conserved N98 residue is enriched with high mannose and sialylated glycans. Hyperglycosylated SLAMF7 was associated with STT3A expression in breast cancer cells. Inhibition of STT3A by a small molecule inhibitor, N-linked glycosylation inhibitor-1 (NGI-1), reduced glycosylation of SLAMF7, resulting in enhancing antibody affinity and phagocytosis. To provide an on-target effect, we developed an antibody-drug conjugate (ADC) by coupling the anti-SLAMF7 antibody with NGI-1. Deglycosylation of SLAMF7 increases antibody recognition and promotes macrophage engulfment of breast cancer cells. Our work suggests deglycosylation by ADC is a potential strategy to enhance the response of immunotherapeutic agents.

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In this study, the researchers aimed to investigate the role of N-linked glycosylation of SLAMF7 (signaling lymphocytic activation molecule family 7) in breast cancer progression. N-linked glycosylation is a post-translational modification that involves the addition of sugar molecules to proteins. It has been observed that N-linked glycosylation of proteins can shield tumor antigens from immune attack, making them less susceptible to recognition and elimination by the immune system.

The researchers identified seven N-linked glycosylation motifs on SLAMF7, and these motifs were predominantly occupied by complex glycan structures. Among these glycans, the N98 residue was found to be enriched with high mannose and sialylated glycans. Furthermore, they found a correlation between the expression of STT3A, an enzyme involved in N-glycosylation, and hyperglycosylation of SLAMF7 in breast cancer cells.

To investigate the functional implications of N-glycosylation on SLAMF7, the researchers used a small molecule inhibitor called N-linked glycosylation inhibitor-1 (NGI-1) to inhibit the activity of STT3A and reduce the glycosylation of SLAMF7. They observed that the inhibition of STT3A resulted in decreased glycosylation of SLAMF7, which in turn enhanced the affinity of antibodies towards SLAMF7 and promoted the phagocytosis (engulfment) of breast cancer cells by macrophages.

To specifically target the deglycosylation of SLAMF7 and enhance the response of immunotherapeutic agents, the researchers developed an antibody-drug conjugate (ADC). They coupled the anti-SLAMF7 antibody with NGI-1, the glycosylation inhibitor, in the ADC. This approach aimed to deliver NGI-1 directly to SLAMF7-expressing breast cancer cells, promoting deglycosylation and enhancing antibody recognition. Consequently, the enhanced antibody recognition facilitated macrophage engulfment of breast cancer cells.

Overall, this study suggests that deglycosylation of SLAMF7 using an ADC approach could be a potential strategy to enhance the response of immunotherapeutic agents in breast cancer treatment. By reducing the shielding effect of N-linked glycans, the antibodies can better recognize SLAMF7-expressing tumor cells, leading to increased phagocytosis and potentially improving the effectiveness of immunotherapy.