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Blood, 15 April 2008, Vol. 111, No. 8, pp. 4233-4244.
Prepublished online as a Blood First Edition Paper on February 13, 2008; DOI 10.1182/blood-2007-07-099226.
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Submitted July 3, 2007
Accepted February 12, 2008
Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T-cell suppressive activity
Kiavash Movahedi, Martin Guilliams, Jan Van den Bossche, Rafael Van den Bergh, Conny Gysemans, Alain Beschin, Patrick De Baetselier, and Jo A Van Ginderachter*
Laboratory of Cellular and Moleclular Immunology, Department of Molecular and Cellular Interactions, VIB, Brussels, Belgium
Laboratory of Cellular and Moleclular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
Laboratory of Experimental Medicine and Endecrinology, Katholieke Universiteit Leuven, Leuven, Belgium
* Corresponding author; email: jvangind{at}vub.ac.be.
The induction of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) is an important immune-evading mechanism employed by tumors. However, the exact nature and function of MDSCs remain elusive, especially because they constitute a heterogeneous population which has not yet been clearly defined. Here, we identified two distinct MDSC subfractions with clear morphologic, molecular and functional differences. These fractions consisted of either mononuclear cells (MO-MDSCs), resembling inflammatory monocytes, or low-density polymorphonuclear cells (PMN-MDSCs), akin to immature neutrophils. Interestingly, both MO-MDSCs and PMN-MDSCs suppressed antigen-specific T-cell responses, albeit by employing distinct effector molecules and signaling pathways. Blocking IFN- or disrupting STAT1 partially impaired suppression by MO-MDSCs, for which nitric oxide (NO) was one of the mediators. In contrast, while IFN- was strictly required for the suppressor function of PMN-MDSCs, this did not rely on STAT1 signaling nor NO production. Finally, MO-MDSCs were shown to be potential precursors of highly anti-proliferative NO-producing mature macrophages. However, distinct tumors differentially regulated this inherent MO-MDSC differentiation program, indicating that this phenomenon was tumor-driven. Overall, our data refine tumor-induced MDSC functions by uncovering mechanistically distinct MDSC subpopulations, potentially relevant for MDSC-targeted therapies.
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