Mediate Inhibition of Natural Killer Cell Cytotoxicity Mucins Bearing the Cancer-associated Sialosyl-Tn Antigen

The sialosyl-Tn (Sin) antigen is a mucin-associated carbohydrate antigen expressed by a variety of adenocarcinomas. In the colon, ex pression of this antigen has been associated with a poor prognosis, independent of tumor stage or histology. The present study was per formed to determine whether this adverse clinical outcome might be due to an interaction between STn-positive murili and natural killer (NK) cell cytotoxicity. Ovine submaxillary mucin (OSM), a mucin highly rich in S l n antigen, partially inhibited NK cell cytotoxicity against K562 target cells, but only at high concentrations. Low concentrations of OSM were not inhibitory but became markedly inhibitory in the pres ence of ammonium ions. Two other STn-positive submaxillary mucins also markedly inhibited NK cytotoxicity when combined with ammo nium ions. Removal of sialic acid from OSM reversed the OSM/ ammonium-mediated inhibition of NK cell activity. Unlike the submax illary mucins, two mucins derived from human breast and lung cancer cells which lack the Sin antigen, did not inhibit NK cell activity in this system. Likewise, four other non-mucin glycoproteins which lack Sin expression did not inhibit NK cells despite having levels of sialic acid that were, in some cases, comparable to submaxillary mucin. These results indicate that mucins bearing the cancer-associated Sin antigen can effectively inhibit NK cell cytotoxicity in the presence of ammonium ions. While this NK cell inhibition is likely to be caused by ammonium, mucin markedly enhances this effect, thereby implicating a novel ¡in munomodulatory property of mucin.