期刊
ONCOTARGET
卷 5, 期 17, 页码 7843-U796出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2279
关键词
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资金
- Instituto de Salud Carlos III, Spain [CP12/03114]
- Refbio transpyrenaic collaborative project grant (NTBM)
- Refbio transpyrenaic collaborative project grant (ncRNAbc)
- Sandra Ibarra Foundation's grant
- BD Bioscience Spring Immunology Award
- FWO-Vlaanderen [1506507N, G.0234.11]
- [PT13/0001]
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 nonneoplastic 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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