A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4+ CD25+ Foxp3+ T cells

B Hoechst, LA Ormandy, M Ballmaier, F Lehner… - Gastroenterology, 2008 - Elsevier
B Hoechst, LA Ormandy, M Ballmaier, F Lehner, C Krüger, MP Manns, TF Greten, F Korangy
Gastroenterology, 2008Elsevier
Background & Aims: Several studies have shown that development of hepatocellular
carcinoma (HCC) generates a number of immune suppressive mechanisms in these
patients. Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells
that have been shown to inhibit T-cell responses in tumor-bearing mice, but little is known
about these cells in humans owing to a lack of specific markers. In this study, we have
investigated the frequency and function of a new population of MDSC denoted here as …
Background & Aims
Several studies have shown that development of hepatocellular carcinoma (HCC) generates a number of immune suppressive mechanisms in these patients. Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that have been shown to inhibit T-cell responses in tumor-bearing mice, but little is known about these cells in humans owing to a lack of specific markers. In this study, we have investigated the frequency and function of a new population of MDSC denoted here as CD14+HLA-DR−/low in HCC patients. We have also identified a novel, MDSC-mediated immune regulatory pathway in these patients.
Methods
We have directly isolated and characterized MDSCs for phenotype and function from peripheral blood (n = 111) and tumor (n = 12) of patients with HCC.
Results
The frequency of CD14+HLA-DR−/low cells in peripheral blood mononuclear cells (PBMC) from HCC patients was significantly increased in comparison with healthy controls. CD14+ HLA-DR−/low cells were unable to stimulate an allogeneic T-cell response, suppressed autologous T-cell proliferation, and had high arginase activity, a hallmark characteristic of MDSC. Most important, CD14+HLA-DR−/low cells from HCC patients induced a CD4+CD25+Foxp3+ regulatory T-cell population when cocultured with autologous T cells.
Conclusion
CD14+HLA-DR−/low cells are a new population of MDSC increased in blood and tumor of HCC patients. We propose a new mechanism by which MDSC exert their immunosuppressive function, through the induction of CD4+CD25+Foxp3+ regulatory T cells in cocultured CD4+ T cells. Understanding the mechanism of action of MDSC in HCC patients is important in the design of effective immunotherapeutic protocols.
Elsevier