PT  - JOURNAL ARTICLE
AU  - Senlian Hong
AU  - Chenhua Yu
AU  - Shi Yujie
AU  - Peng Wang
AU  - Digantkumar G. Chapla
AU  - Emily Rodrigues
AU  - Kelly W. Moremen
AU  - James C. Paulson
AU  - Matthew S. Macauley
AU  - Peng Wu
TI  - Modulation of Siglec-7 Signaling via <em>in situ</em> Created High-affinity <em>cis</em>-Ligands
AID  - 10.1101/2020.07.15.203125
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.15.203125
4099  - http://biorxiv.org/content/early/2020/09/01/2020.07.15.203125.short
4100  - http://biorxiv.org/content/early/2020/09/01/2020.07.15.203125.full
AB  - Sialic acid-binding immunoglobulin-like lectins, also known as Siglecs, have recently been designated as glyco-immune checkpoints. Through their interactions with sialylated glycan epitopes overexpressed on tumor cells, inhibitory Siglecs on innate and adaptive immune cells modulate signaling cascades to restrain anti-tumor immune responses. However, the mechanisms underlying these processes are just starting to be elucidated. We discover that when human natural killer (NK) cells attack tumor cells, glycan remodeling occurs on the target cells at the immunological synapse. This remodeling occurs through both transfer of sialylated glycans from NK cells to target tumor cells and accelerated de novo synthesis of sialosides on the tumor cell themselves. The functionalization of NK cells with a high-affinity ligand of Siglec-7 leads to multifaceted consequences in modulating Siglec-7-regulated NK-activation. At high levels, the added Siglec-7 ligand suppresses NK-cytotoxicity through the recruitment of Siglec-7, whereas at low levels the same ligand triggers the release of Siglec-7 from the cell surface into the culture medium, preventing Siglec-7-mediated inhibition of NK cytotoxicity. These results suggest that glycan engineering of NK cells may provide a means to boost NK effector functions.Competing Interest StatementThe authors have declared no competing interest.