Melanoma-Educated CD14+ Cells Acquire a Myeloid-Derived Suppressor Cell Phenotype through COX-2-Dependent Mechanisms

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 13; pp. 3877 - 3887
• Main Authors: MAO, Yumeng, POSCHKE, Isabel, WENNERBERG, Erik, DE COANA, Yago Pico, BRAGE, Suzanne Egyhazi, SCHULTZ, Inkeri, HANSSON, Johan, MASUCCI, Giuseppe, LUNDQVIST, Andreas, KIESSLING, Rolf
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.07.2013
• Subjects: Antigens, CD - metabolism; Antineoplastic agents; Biological and medical sciences; Cancer och onkologi; Cell Line, Tumor; Coculture Techniques; Cyclooxygenase 2 - metabolism; Dermatology; Dinoprostone - biosynthesis; HLA-DR Antigens - metabolism; Humans; Immune Tolerance; Immunologi inom det medicinska området; Klinisk medicin; Leukocytes, Mononuclear - enzymology; Lipopolysaccharide Receptors - metabolism; Medical sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Melanoma - immunology; Melanoma - pathology; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Myeloid Cells - enzymology; Myeloid Cells - immunology; Pharmacology. Drug treatments; Phenotype; Signal Transduction; STAT3 Transcription Factor - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - physiology; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Up-Regulation; Phenotype; Myeloid derived suppressor cell; Enzyme; Cyclooxygenase 2; Malignant melanoma; Oxidoreductases; Malignant tumor; Mechanism of action; In vitro; Cancer
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.can-12-4115

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.