Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity.
The induction of CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) is an important immune-evading mechanism used by tumors. However, the exact nature and function of MDSCs remain elusive, especially because they constitute a heterogeneous population that has not yet been clearly defined. Here, we identified 2 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 using distinct effector molecules and signaling pathways. Blocking IFN-gamma or disrupting STAT1 partially impaired suppression by MO-MDSCs, for which nitric oxide (NO) was one of the mediators. In contrast, while IFN-gamma was strictly required for the suppressor function of PMN-MDSCs, this did not rely on STAT1 signaling or NO production. Finally, MO-MDSCs were shown to be potential precursors of highly antiproliferative 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.
Movahedi
Kiavash
K
Laboratory of Cellular and Molecular Immunology, Department of Molecular and Cellular Interactions, VIB, Brussels, Belgium.
Guilliams
Martin
M
Van den Bossche
Jan
J
Van den Bergh
Rafael
R
Gysemans
Conny
C
Beschin
Alain
A
De Baetselier
Patrick
P
Van Ginderachter
Jo A
JA
D000818:Animals; D015415:Biomarkers; D039481:CD11b Antigen / Q000276:immunology; D002454:Cell Differentiation; D002460:Cell Line; D000939:Epitopes / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology* / Q000276:immunology; D009369:Neoplasms / Q000473:pathology*; D010641:Phenotype; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D013234:Stem Cells / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology
D015415:Biomarkers; D039481:CD11b Antigen; D000939:Epitopes; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007371:Interferon-gamma