Despite major advances toward an improved understanding of the mechanisms leading to tumor immunity, the successful translation of mechanistic insights into effective tumor immunotherapy is hindered by a number of immunological obstacles. These include the ability of tumors to foster a tolerant microenvironment and the activation of a plethora of immunosuppressive mechanisms, which may act in concert to counteract effective immune responses. Here we will discuss different strategies employed by tumors to thwart immune responses, including tumor-induced impairment of antigen presentation, activation of negative costimulatory signals and elaboration of immunosuppressive and pro-apopoptic factors. In addition, we will underscore the influence of regulatory cell populations that may contribute to this immunosuppressive network including regulatory T cells, NKT cells and distinct subsets of immature and mature dendritic cells. The current wealth of preclinical information promises a future scenario in which the synchronized blockade of immunosuppressive mechanisms and the removal of inhibitory signals might be effective in combination with other conventional strategies to overcome immunological tolerance and promote tumor regression.

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Myeloid-derived suppressor cells (MDSC) are a major component of the immune suppressive network described in cancer and many other pathological conditions. Recent studies have demonstrated that one of the major mechanisms of MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). However, the mechanism of this phenomenon remained unknown. In this study, we observed a substantial up-regulation of ROS by MDSC in all of seven different tumor models and in patients with head and neck cancer. The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). MDSC from tumor-bearing mice had significantly higher expression of NOX2 subunits, primarily p47phox and gp91phox, compared with immature myeloid cells from tumor-free mice. Expression of NOX2 subunits in MDSC was controlled by the STAT3 transcription factor. In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. These findings expand our fundamental understanding of the biology of MDSC and may also open new opportunities for therapeutic regulation of these cells in cancer.