title: Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms.
abstract: Tumors can suppress the host immune system by employing a variety of cellular immune modulators, such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells (MDSC). In the peripheral blood of patients with advanced stage melanoma, there is an accumulation of CD14(+)HLA-DR(lo/-) MDSC that suppress autologous T cells ex vivo in a STAT-3-dependent manner. However, a precise mechanistic basis underlying this effect is unclear, particularly with regard to whether the MDSC induction mechanism relies on cell-cell contact of melanoma cells with CD14(+) cells. Here, we show that early-passage human melanoma cells induce phenotypic changes in CD14(+) monocytes, leading them to resemble MDSCs characterized in patients with advanced stage melanoma. These MDSC-like cells potently suppress autologous T-cell proliferation and IFN-γ production. Notably, induction of myeloid-suppressive functions requires contact or close proximity between monocytes and tumor cells. Further, this induction is largely dependent on production of cyclooxygenase-2 (COX-2) because its inhibition in these MDSC-like cells limits their ability to suppress T-cell function. We confirmed our findings with CD14(+) cells isolated from patients with advanced stage melanoma, which inhibited autologous T cells in a manner relying up prostaglandin E2 (PGE2), STAT-3, and superoxide. Indeed, PGE2 was sufficient to confer to monocytes the ability to suppress proliferation and IFN-γ production by autologous T cells ex vivo. In summary, our results reveal how immune suppression by MDSC can be initiated in the tumor microenvironment of human melanoma.
authors: Cancer Center Karolinska, Institution of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors: Yumeng
authors: Y
authors: Mao
authors: Isabel
authors: I
authors: Poschke
authors: Erik
authors: E
authors: Wennerberg
authors: Yago
authors: Y
authors: Pico de Coaña
authors: Suzanne
authors: S
authors: Egyhazi Brage
authors: Inkeri
authors: I
authors: Schultz
authors: Johan
authors: J
authors: Hansson
authors: Giuseppe
authors: G
authors: Masucci
authors: Andreas
authors: A
authors: Lundqvist
authors: Rolf
authors: R
authors: Kiessling
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007963:Leukocytes, Mononuclear / Q000201:enzymology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D022423:Myeloid Cells / Q000201:enzymology* / Q000276:immunology; D010641:Phenotype; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D006684:HLA-DR Antigens; D018950:Lipopolysaccharide Receptors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone