Urokinase-mediated recruitment of myeloid-derived suppressor cells and their suppressive mechanisms are blocked by MUCl/sec

摘要

The transmembrane isoform of mucin (MUC/TM) is a well-recognized tumor antigen, contributing to tumorigenesis and immune evasion. Although MUC/TM has been correlated with malignancy, we have previously reported on antitumor properties and prevention of tumor development by a secreted splice variant of MUC (MUC/sec). Because myeloid-derived suppressor cells (MDSCs) play a critical role in tumor-induced immunosup-pression, we investigated their recruitment by tumor cells expressing eitherMUC/TM or MUC/sec. DA- tumor cells expressing MUC/sec recruit dramatically lower levels of MDSCs, relative to MUC/TM-expressing DA- cells. Because MUC/sec was previously shown to down-regulate tumor expression of urokinase plasminogen activator (uPA), a protease linked to tumor aggressiveness and metastasis, the potential role of uPA in MDSC recruitment was investigated. Tumor-derived uPA is capable of recruiting MDSCs, and correlates with tumor development. In addition to diminishing recruitment ofMDSCs, the effect of MUC/sec on MDSC-suppressive mechanisms was investigated. MUC/sec, or its unique immunoenhancing peptide, is capable of blocking expression of arginase and production of reactive oxygen species in MDSCs, implicated in the suppression of T cells. These findings demonstrate a new mechanism of MDSC recruitment, and provide evidence that MUC/sec has antitumor properties affecting MDSCs.