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: An Official Publication of the Reticuloendothelial Society

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 】

Recentstudiessuggestthattumor‐infiltratedmyeloidcellsfrequentlyup‐regulateCOX‐2expressionandhaveenhancedPGE2metabolism.Thismayaffectthematurationandimmunefunctionoftumor‐infiltratedantigen‐presentingcells.Invitrostudiesdemonstratethattumor‐derivedfactorscanskewGM‐CSF‐drivendifferentiationofTh1‐orientedmyeloidAPCsintoM2‐orientedLy6C+F4/80+MDSCsorLy6C–F4/80+arginase‐expressingmacrophages.ThesechangesenablemyeloidcellstoproducesubstantialamountsofIL‐10,VEGF,andMIP‐2.Thetumor‐mediatedinhibitionofAPCdifferentiationwasassociatedwiththeup‐regulatedexpressionofPGE2‐formingenzymesCOX‐2,mPGES1inmyeloidcells,andthesimultaneousrepressionofPGE2‐catabolizingenzyme15‐PGDH.Thepresenceoftumor‐derivedfactorsalsoledtoareducedexpressionofPGTbutpromotedtheup‐regulationofMRP4,whichworksasaPGE2effluxreceptor.AdditionofCOX‐2inhibitortotheBMcellculturescouldpreventthetumor‐inducedskewingofmyeloidcelldifferentiation,partiallyrestoringcellphenotypeanddown‐regulatingthearginaseexpressioninthemyeloidAPCs.OurstudysuggeststhattumorsimpairtheintracellularPGE2catabolisminmyeloidcellsthroughsimultaneousstimulationofPGE2‐formingenzymesandinhibitionofPGE2‐degradingsystems.Thistumor‐induceddichotomydrivesthedevelopmentofM2‐oriented,arginase‐expressingmacrophagesortheMDSC,whichcanbeseenfrequentlyamongtumor‐infiltratedmyeloidcells...

【 授权许可】

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