Pivotal Advance: Tumor-mediated induction of myeloid-derived suppressor cells and M2-polarized macrophages by altering intracellular PGE2 catabolism in myeloid cells

Journal of Leukocyte Biology

Johannes Vieweg¹  Irina Daurkin¹  Sergei Kusmartsev¹  Javier Ortiz¹  Evgeniy Eruslanov¹ 

[1] Shands Cancer Center and Department of Urology, University of Florida, College of Medicine, Gainesville, Florida, USAShands Cancer Center and Department of Urology, University of Florida, College of Medicine, Gainesville, Florida, USAShands Cancer Center and Department of Urology, University of Florida, College of Medicine, Gainesville, Florida, USA

关键词: COX-2;    15-PGDH;    microenvironment;    lipid mediators;    cancer;   

DOI  :  10.1189/jlb.1209821

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Recent studies suggest that tumor-infiltrated myeloid cells frequently up-regulate COX-2 expression and have enhanced PGE2 metabolism. This may affect the maturation and immune function of tumor-infiltrated antigen-presenting cells. In vitro studies demonstrate that tumor-derived factors can skew GM-CSF-driven differentiation of Th1-oriented myeloid APCs into M2-oriented Ly6C+F4/80+ MDSCs or Ly6C–F4/80+ arginase-expressing macrophages. These changes enable myeloid cells to produce substantial amounts of IL-10, VEGF, and MIP-2. The tumor-mediated inhibition of APC differentiation was associated with the up-regulated expression of PGE2-forming enzymes COX-2, mPGES1 in myeloid cells, and the simultaneous repression of PGE2-catabolizing enzyme 15-PGDH. The presence of tumor-derived factors also led to a reduced expression of PGT but promoted the up-regulation of MRP4, which works as a PGE2 efflux receptor. Addition of COX-2 inhibitor to the BM cell cultures could prevent the tumor-induced skewing of myeloid cell differentiation, partially restoring cell phenotype and down-regulating the arginase expression in the myeloid APCs. Our study suggests that tumors impair the intracellular PGE2 catabolism in myeloid cells through simultaneous stimulation of PGE2-forming enzymes and inhibition of PGE2-degrading systems. This tumor-induced dichotomy drives the development of M2-oriented, arginase-expressing macrophages or the MDSC, which can be seen frequently among tumor-infiltrated myeloid cells.

【 授权许可】

Unknown