Journal
IMMUNOLOGICAL INVESTIGATIONS
Volume 41, Issue 6-7, Pages 635-657Publisher
TAYLOR & FRANCIS INC
DOI: 10.3109/08820139.2012.695417
Keywords
PGE(2); COX2; arginase; inducible NOS; ROS; immunosuppression; tolerance; prostaglandins; cytokines; chemokines; interferons; macrophages; dendritic cells; myeloid-derived suppressor cells; inflammation; cancer; immunopathology; immunotherapy
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Funding
- NIH [1PO1 CA132714, 5T32 CA082084]
- DOD [W81XWH-09-2-0051]
- UICC American Cancer Society
- American Cancer Society
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Myeloid-derived suppressor cells (MDSCs) are critical mediators of tumor-associated immune suppression, with their numbers and activity strongly increased in most human cancers and animal models. MDSCs suppress anti-tumor immunity through multiple mechanisms, including the manipulation of arginine and tryptophan metabolism by such factors as arginase (Arg), inducible nitric oxide synthase (iNOS/NOS2), and indoleamine-2,3-dioxygenase (IDO). Prostaglandin E-2 (PGE(2)), a mediator of chronic inflammation and tumor progression, has emerged as a key molecule in MDSC biology. PGE(2) promotes MDSC development and their induction by additional factors, directly suppresses T cell immune responses and participates in the induction of other MDSC-associated suppressive factors, including Arg, iNOS and IDO. It further promotes MDSC recruitment to tumor environments through the local induction of CXCL12/SDF-1 and the induction and stabilization of the CXCL12 receptor, CXCR4, on tumor-associated MDSCs. The establishment of a positive feedback loop between PGE(2) and cyclooxygenase 2 (COX-2), the key regulator of PGE(2) synthesis, stabilizes the MDSC phenotype and is required for their suppressive function. The central role of PGE(2) in MDSC biology provides for a feasible target for counteracting MDSC-mediated immune suppression in cancer.
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