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 þ HLA-DR lo/À 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 þ cells. Here, we show that early-passage human melanoma cells induce phenotypic changes in CD14 þ 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-g 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 þ cells isolated from patients with advanced stage melanoma, which inhibited autologous T cells in a manner relying up prostaglandin E2 (PGE 2 ), STAT-3, and superoxide. Indeed, PGE 2 was sufficient to confer to monocytes the ability to suppress proliferation and IFN-g 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. Cancer Res; 73(13); 3877-87. Ó2013 AACR.

Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

“…Primary human monocytes were cocultured with human neuroblastoma cell lines according to our published protocol (35). In brief, monocytes were cocultured with 4Â10…”

“…CSF-1R blockade reverted suppressive functions on tumoreducated human monocytes Next, we cocultured primary monocytes freshly isolated from healthy individuals with three human neuroblastoma cell lines, according to our previously published protocol (35). This coculture model allowed us to dissect the impact of tumor-derived factors on myeloid cells that are recruited into the neuroblastoma tumor microenvironment.…”

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

“…Two isoforms of COX are referred to as COX-1 and COX-2. 24 COX-1 is a constitutively expressed housekeeping gene, whereas COX-2 expression is normally restricted to a few organs but can be induced by a variety of stimuli, including cytokines, oncogenes, growth factors, and hormones. 25,26 Increased expression of COX-2 is frequently detected in many cancers, including NPC.…”

“…COX-2 is an inducible enzyme that produces PGs in inflammatory and tumorigenic settings. 24,27 This function of the COX-2/ PGE2 pathway affects multiple aspects of cell physiology required for tumor development. The involvement of COX-2 in the induction of MDSCs in tumor hosts and tumor metastasis has been documented in recent years; 28,29 however, the link between COX-2, MDSCs and tumor metastasis and its mechanism of regulation in tumors is unknown.…”

Macrophages in skin melanoma-the key element in melanomagenesis (Review)

“…IL-10 and TGFβ are produced by TAMs, which inhibit the differentiation of bone marrow cells into dendritic cells, determining their further differentiation into TAMs (25). Furthermore, the combination of factors produced by melanoma-associated macrophages induce the activity of the myeloid-derived suppressor cells that additionally inhibit the response of the immune system (32). It should be noted that within TAMs, similar to melanoma cells, there is a high expression of PD-L1 that helps TAM and regulatory T lymphocytes to form an immunosuppressive microenvironment (33,34) (Fig.…”