Myeloid-derived suppressive cells (MDSCs) are potent immune suppressive cells that accumulate with tumor progression. Compelling data from mouse models and human cancer patients have shown that tumor-induced inflammation induces MDSC differentiation. However, the mechanisms underlying MDSC persistence is unknown. Here, we made use of orthotopic mammary and colon carcinoma mouse tumor models and demonstrated that tumor-induced MDSCs exhibit significantly decreased spontaneous apoptosis in vivo, as well as decreased sensitivity to FasL-induced apoptosis in vitro, as compared to myeloid cells with the same phenotype from tumor-free mice. Furthermore, tumor-induced MDSCs accumulated in a greater rate in Faslgld mice than in wild type mice. Analysis of gene expression profiles revealed that IRF8 is dramatically down-regulated in MDSCs from tumor-bearing mice and from human cancer patients as compared to tumor-free mice and normal human donors, respectively. Further analysis of IRF8 target gene expression indicated that Fas and Bax are down-regulated, whereas Bcl-xL is up-regulated in MDSCs from tumor-bearing mice. ABT-737 therapy increased MDSCs spontaneous apoptosis and decreased MDSC accumulation in vivo. Our data determine that MDSCs use down-regulation of IRF8 to deregulate the Fas-mediated apoptosis pathway to evade elimination by apoptosis in tumor-bearing hosts, and targeting Bcl-xL is potentially an effective approach to suppress MDSC persistence in cancer therapy.
- Copyright © 2013 by The American Association of Immunologists, Inc.