Tumor-induced myeloid-derived suppressor cells promote tumor progression through oxidative metabolism in human colorectal cancer

Abstract

BackgroundExpansions of myeloid-derived suppressor cells (MDSCs) have been identified in human solid tumors, including colorectal cancer (CRC). However, the nature of these tumor-associated MDSCs and their interactions with tumor cells in CRC are still poorly understood.MethodsThe percentages and phenotype of MDSCs in peripheral blood and tumorous and paraneoplastic tissues from CRC patients, as well as the clinical relevance of these MDSCs, were assessed. Age-matched healthy donors were included as controls. The interaction between MDSCs and T cells or tumor cells was investigated in a coculture system in vitro, and the molecular mechanism of the effect of MDSCs on T cells or tumor cells was evaluated.ResultsWe discovered that CRC patients had elevated levels of CD33+CD11b+HLA-DR− MDSCs in primary tumor tissues and in peripheral blood, and the elevated circulating MDSCs were correlated with advanced TNM stages and lymph node metastases. Radical resection significantly decreases the proportions of circulating MDSCs and CD4+CD25highFOXP3+ regulatory T cells. In vitro, CRC cells mediate the promotion of MDSC induction. Moreover, these tumor-induced MDSCs could suppress T cell proliferation and promote CRC cell growth via cell-to-cell contact. Such effects could be abolished by the inhibition of oxidative metabolism, including the production of nitric oxide (NO), and reactive oxygen species (ROS).ConclusionsOur results reveal the functional interdependence between MDSCs, T cells and cancer cells in CRC pathogenesis. Understanding the impact of MDSCs on T cells and tumor cells will be helpful to establish an immunotherapeutic strategy in CRC patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0410-7) contains supplementary material, which is available to authorized users.

Ranitidine modifies myeloid cell populations and inhibits breast tumor development and spread in mice

“…Increases in circulating MDSCs correlate with disease progression in breast cancer patients 65 and circulating MDSCs in cancer patients are shown to inhibit T cell proliferation 64,65 . In our experiments, blood leukocytes from ranitidine-treated 4T1 tumor-bearing mice had less suppressive activity on antigen-driven T cell proliferation than those from control tumor bearing mice.…”

TNF Receptor-2 Facilitates an Immunosuppressive Microenvironment in the Liver to Promote the Colonization and Growth of Hepatic Metastases

“…This suggests that the reduction in arginase activity observed in these cells may have been related to the increase in the proportion of apoptotic and preapoptotic cells, although other mechanisms compromising their activity cannot, at present, be ruled out. Recruitment of tumor-promoting myeloid cells into colorectal carcinoma tumors (36) and liver metastases (49,50) has recently been reported by others. However, full characterization of these cells in hepatic metastases has been lacking.…”

Clinical Significance of Circulating CD33+CD11b+HLA-DR− Myeloid Cells in Patients with Stage IV Melanoma Treated with Ipilimumab

“…S1A; refs. 15,17,18,24). Analysis of blood samples taken before the first ipilimumab treatment showed that the percentages of CD33 þ CD11b þ HLA-DR À MDSCs in the group of patients with melanoma was significantly higher (48.8 AE 2.3, P < 0.0001) as compared with HD (27.9 AE 1.7; Fig.…”