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Abstract
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 E2 (PGE2), a mediator of chronic inflammation and tumor progression, has emerged as a key molecule in MDSC biology. PGE2 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 PGE2 and cyclooxygenase 2 (COX-2), the key regulator of PGE2 synthesis, stabilizes the MDSC phenotype and is required for their suppressive function. The central role of PGE2 in MDSC biology provides for a feasible target for counteracting MDSC-mediated immune suppression in cancer.
ACKNOWLEDGMENTS
This work was supported by NIH grants 1PO1 CA132714 (P.K.) and 5T32 CA082084 (J.L.W.), DOD grant W81XWH-09-2-0051 (P.K.), and by a UICC American Cancer Society Beginning Investigators Fellowship funded by the American Cancer Society (N.O.).
Declaration of Interest: Authors declare no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Notes
N.O. and J.L.W. equally contributed to this work.
