Bidirectional signals generated by Siglec-7 and its crucial ligand tri-sialylated T to escape of cancer cells from immune surveillance

• Published in: iScience Vol. 27; no. 11; p. 111139
• Main Authors: Hashimoto, Noboru, Ito, Shizuka, Harazono, Akira, Tsuchida, Akiko, Mouri, Yasuhiro, Yamamoto, Akihito, Okajima, Tetsuya, Ohmi, Yuhsuke, Furukawa, Keiko, Kudo, Yasusei, Kawasaki, Nana, Furukawa, Koichi
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 15-11-2024; Elsevier
• Subjects: Cancer; Glycobiology; Immune response; Glycobiology; Immune response; Cancer
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.111139

Siglec-7, an inhibitory receptor expressed on natural killer (NK) cells, recognizes sialic acid-containing glycans. However, the ligand glycan structures of Siglec-7 and its carrier proteins have not been comprehensively investigated. Here, we identified four sialyltransferases that are used for the synthesis of ligand glycans of Siglec-7 and two ligand O-glycan-carrier proteins, PODXL and MUC13, using a colon cancer line. Upon binding of these ligand glycans, Siglec-7-expressing immune cells showed reduced cytotoxic activity, whereas cancer cells expressing ligand glycans underwent signal activation, leading to enhanced invasion activity. To clarify the structure of the ligand glycan, podoplanin (PDPN) identified as a Siglec-7 ligand-carrier protein, was transfected into HEK293T cells using sialyltransferase cDNAs. Mass spectrometry of the products revealed a ligand glycan, tri-sialylated T antigen. These results indicate that Siglec-7 interaction with its ligand generates bidirectional signals in NK and cancer cells, leading to the efficient escape of cancers from host immune surveillance.
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•Siglec-7 inhibits cytotoxicity via the molecules identified as ligand glycan-carrier•The molecules enhance metastatic property of cancer cell by binding of Siglec-7•Sialyltransferase genes that synthesize the ligand relate a poor prognosis in cancer•The ligand structure is revealed to be a tri-sialyl T antigen
Cancer; Glycobiology; Immune response