A highly efficient tumor-infiltrating MDSC differentiation system for discovery of anti-neoplastic targets, which circumvents the need for tumor establishment in mice
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Therese Liechtenstein1,2, Noemi Perez-Janices1,3, Maria Gato2, Fabio Caliendo2, Grazyna Kochan2, Idoia Blanco-Luquin3, Kevin Van der Jeught5, Frederick Arce1, David Guerrero-Setas3, Joaquin Fernandez-Irigoyen4, Enrique Santamaria4, Karine Breckpot5, David Escors1,2
1 Division of infection and immunity. Rayne Institute. 5 University Street. WC1E 6JF. London. UK.
2 Immunomodulation group. Navarrabiomed-FMS, calle Irunlarrea 3, 31008 Pamplona, Navarra, Spain.
3 Cancer Epigenetics group. Navarrabiomed-FMS, calle Irunlarrea 3, 31008 Pamplona, Navarra, Spain.
4 Proteomics Unit. Navarrabiomed-FMS, calle Irunlarrea 3, 31008 Pamplona, Navarra, Spain.
5 Laboratory of Molecular and Cellular Therapy. Department of Biomedical Sciences. Laarbeeklaan, 103/E, B-1090 Jette. Vrije Universiteit Brussel, Belgium.
Received: June 29, 2014 Accepted: July 29, 2014 Published: August 4, 2014
Myeloid-derived suppressor cells (MDSCs) exhibit potent immunosuppressive activities in cancer. MDSCs infiltrate tumors and strongly inhibit cancer-specific cytotoxic T cells. Their mechanism of differentiation and identification of MDSC-specific therapeutic targets are major areas of interest. We have devised a highly efficient and rapid method to produce very large numbers of melanoma-infiltrating MDSCs ex vivo without inducing tumors in mice. These MDSCs were used to study their differentiation, immunosuppressive activities and were compared to non-neoplastic counterparts and conventional dendritic cells using unbiased systems biology approaches. Differentially activated/deactivated pathways caused by cell type differences and by the melanoma tumor environment were identified. MDSCs increased the expression of trafficking receptors to sites of inflammation, endocytosis, changed lipid metabolism, and up-regulated detoxification pathways such as the expression of P450 reductase. These studies uncovered more than 60 potential novel therapeutic targets. As a proof of principle, we demonstrate that P450 reductase is the target of pro-drugs such as Paclitaxel, which depletes MDSCs following chemotherapy in animal models of melanoma and in human patients. Conversely, P450 reductase protects MDSCs against the cytotoxic actions of other chemotherapy drugs such as Irinotecan, which is ineffective for the treatment of melanoma.
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