Tumor cell-intrinsic and tumor microenvironmental conditions co-determine signaling by the glycoimmune checkpoint receptor Siglec-7

• DOI: 10.1007/s00018-023-04816-6
• Publication Date: 2023-05-30T17:02:17Z
• Authors: Eline J. H. van H...; Esther D. Kers-Rebel; Maaike W. Looman; Erik Hooijberg; Christian Büll; Daniel Granado; Lenneke A. M. Cor...; Gosse J. Adema
• Keywords: SIGLEC; Cell Signaling

Tumors create an immunosuppressive tumor microenvironment by altering protein expression, but also changing their glycosylation status, like altered expression of sialoglycans. Sialoglycans are capped with sialic acid sugar residues and recognized Siglec immune receptors. Siglec-7 is inhibitory receptor similar to PD-1, emerging as glycoimmune checkpoint exploited cancer cells evade the system. However, exact cellular molecular conditions required for Siglec-7-mediated cell inhibition remain largely unknown. Here, we report on development a chimeric system that enables dissection signaling, rather than binding. Antibody-induced clustering, acid-containing polymers, highly sialylated erythrocytes effectively induced thereby validating functionality this reporter Moreover, reveals cell-dependent signaling. Tumor-associated important signaling were defined, such ligand levels, presence known CD43, availability sialylation glycans. Importantly, therapeutic targeting Siglec-7/sialic axis using sialyltransferase inhibitor resulted in strong reduction In conclusion, newly established tool, defined set tumor-associated influence allows assess efficacy novel drugs interfering immunotherapy treat cancer.