Submitted August 28, 2008
Accepted January 27, 2009
Urokinase-mediated recruitment of myeloid-derived suppressor cells and their suppressive mechanisms are blocked by MUC1/sec
Dan Ilkovitch and Diana M. Lopez*
Department of Microbiology & Immunology, Miller School of Medicine, University of Miami, Miami, FL, United States
Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United States
* Corresponding author; email: dlopez{at}med.miami.edu.
The transmembrane isoform of mucin 1 (MUC1/TM) is a well recognized tumor antigen, contributing to tumorigenesis and immune evasion. While MUC1/TM has been correlated with malignancy, we have previously reported on antitumor properties and prevention of tumor development by a secreted splice variant of MUC1 (MUC1/sec). Since myeloid-derived suppressor cells (MDSC) play a critical role in tumor-induced immunosuppression, we investigated their recruitment by tumor cells expressing either MUC1/TM or MUC1/sec. DA-3 tumor cells expressing MUC1/sec recruit dramatically lower levels of MDSC, relative to MUC1/TM expressing DA-3 cells. Since MUC1/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 MDSC, and correlates with tumor development. In addition to diminishing recruitment of MDSC, the effect of MUC1/sec on MDSC suppressive mechanisms was investigated. MUC1/sec, or its unique immunoenhancing peptide (IEP), is capable of blocking expression of arginase 1 and production of reactive oxygen species (ROS) in MDSC, implicated in the suppression of T cells. These findings demonstrate a new mechanism of MDSC recruitment, and provide evidence that MUC1/sec has antitumor properties affecting MDSC.
