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  • Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms.

Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms.

Cancer research (2013-05-02)
Yumeng Mao, Isabel Poschke, Erik Wennerberg, Yago Pico de Coaña, Suzanne Egyhazi Brage, Inkeri Schultz, Johan Hansson, Giuseppe Masucci, Andreas Lundqvist, Rolf Kiessling
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Prostaglandin E2, synthetic, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Prostaglandin E2, γ-irradiated, powder, BioXtra, suitable for cell culture
Sigma-Aldrich
Prostaglandin E2, ≥93% (HPLC), synthetic
Dinoprostone, European Pharmacopoeia (EP) Reference Standard