title: A highly efficient tumor-infiltrating MDSC differentiation system for discovery of anti-neoplastic targets, which circumvents the need for tumor establishment in mice.
abstract: 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.
authors.affiliation: Division of infection and immunity, Rayne Institute, 5 University Street, London, UK. Immunomodulation group, Navarrabiomed-FMS, calle Irunlarrea 3, Pamplona, Navarra, Spain.
authors.forename: Therese
authors.initials: T
authors.lastname: Liechtenstein
authors.affiliation: Division of infection and immunity, Rayne Institute, 5 University Street, London, UK. Cancer Epigenetics group, Navarrabiomed-FMS, calle Irunlarrea 3, Pamplona, Navarra, Spain.
authors.forename: Noemi
authors.initials: N
authors.lastname: Perez-Janices
authors.affiliation: Immunomodulation group, Navarrabiomed-FMS, calle Irunlarrea 3, Pamplona, Navarra, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Gato
authors.affiliation: Immunomodulation group, Navarrabiomed-FMS, calle Irunlarrea 3, Pamplona, Navarra, Spain.
authors.forename: Fabio
authors.initials: F
authors.lastname: Caliendo
authors.affiliation: Immunomodulation group, Navarrabiomed-FMS, calle Irunlarrea 3, Pamplona, Navarra, Spain.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Kochan
authors.affiliation: Cancer Epigenetics group, Navarrabiomed-FMS, calle Irunlarrea 3, Pamplona, Navarra, Spain.
authors.forename: Idoia
authors.initials: I
authors.lastname: Blanco-Luquin
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Laarbeeklaan, 103/E, Jette, Vrije Universiteit Brussel, Belgium.
authors.forename: Kevin
authors.initials: K
authors.lastname: Van der Jeught
authors.affiliation: Division of infection and immunity, Rayne Institute, 5 University Street, London, UK.
authors.forename: Frederick
authors.initials: F
authors.lastname: Arce
authors.affiliation: Cancer Epigenetics group, Navarrabiomed-FMS, calle Irunlarrea 3, Pamplona, Navarra, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Guerrero-Setas
authors.affiliation: Proteomics Unit, Navarrabiomed-FMS, calle Irunlarrea 3, Pamplona, Navarra, Spain.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Fernandez-Irigoyen
authors.affiliation: Proteomics Unit, Navarrabiomed-FMS, calle Irunlarrea 3, Pamplona, Navarra, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Santamaria
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Laarbeeklaan, 103/E, Jette, Vrije Universiteit Brussel, Belgium.
authors.forename: Karine
authors.initials: K
authors.lastname: Breckpot
authors.affiliation: Division of infection and immunity, Rayne Institute, 5 University Street, London, UK. Immunomodulation group, Navarrabiomed-FMS, calle Irunlarrea 3, Pamplona, Navarra, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Escors
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques / Q000379:methods*; D002454:Cell Differentiation; D002478:Cells, Cultured; D019295:Computational Biology / Q000379:methods; D003713:Dendritic Cells / Q000166:cytology; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D008545:Melanoma / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology*; D040901:Proteomics / Q000379:methods*