肿瘤微环境中免疫与炎症的调节-黄波

http//．biother．orgChinJCancerBiotherApr．2012Vol．19No．2DOI10．3872/j．issn．1007-385X．2012．02．001··430030、。2002Karo-linskaInstitute、UniversityofCalgaryMountSinaiSchoolofMedicine2006。、T、。Blood、EMBORep、CancerRes、JImmunol、ClinCancerRes、JBiolChem、PLoSOne27Oncogene、CancerMetastasisRev、CellMolImmunol。6、70、2TregTh17、、。[e-mail]。myeloidderivedsuppressorcellMDSCTregulatoryTcellTregMDSCTregToll。。R730．2R730．3A1007-385X201202-0111-05No．30871020No．NCET-08-0219No．30911120482。ProjectsupportedbytheNationalNaturalScienceFoundationofChinaNo．30871020theProgramforNewCenturyEx-cellentTalentsinUniversityNo．NCET-08-0219andtheInternationalCooperationandExchangeoftheNationalNaturalScienceFoundationofChinaNo．30911120482http//．cnki．net/kcms/detail/31．1725．R．20120328．1620．010．htmlRegulationofimmuneresponseandinflammationintumormicroenvironmentHUANGBoDepartmentofBiochemistryandMolecularBiologyTongjiMedicalCollegeHuazhongUniversityofScienceandTechnologyWuhan430030HubeiChinaAbstractImmuneresponseandinflammationcomposestwocoresoftumormicroenvironment．Howevertherelationshipbetweenthemremainselusive．StudiescorroboratetheideathatthemissionofmyeloidderivedsuppressorcellsMDSCsandregulatoryTcellsTregsthatmigratetotumorsitesistosuppressinflammationratherthanmediatetumorimmuneeva-sion．MastcellshowevermediatethecrosstalkofimmuneresponseandinflammationbyregulatingMDSCsandTregs．InadditionToll-likesignalingasthebasicsignalingpathwayintumormicroenvironmentmaydirectlyregulateimmunere-sponseandinflammationmaintaininginflammatoryhomeostasisthroughmicroparticlepathways．Despitetheverycomplexrelationshipbetweenimmuneresponseandinflammationwesuggestthatantitumorimmuneresponseandinflammationarenegativelycorrelatedandtimedependent．Attheearlystageoftumorantitumorimmuneresponsesaredominant．Laterthebiasfavorsinflammationintumormicroenvironment．KeywordstumormicroenvironmentimmuneresponseinflammationregulatorymechanismChinJCancerBiother2012192111-115·111·20124192HanahanWeinberg“Thehallmarksofcancer”、、1。、tumormicroenvironment。10WeinbergHanahanCell“HallmarksofcancerThenextgeneration”2、。、3。。11～2mmVEGF23。T、myeloidderivedsuppressorcellMDSC、、、、B。。、ma-trixmetalloproteinaseMMPB1highmobilitygroupbox1proteinHMGB14-5。MDSC、TregulatoryTcellTreg、tumorassociatedmacrophageTAMIL-6、IL-10、TGF-β、MMP、6。、、。。1。。MDSC7。MC26MDSC6%8MDSC。MDSCT1MDSCTh1iNOSNOT2MDSCTh21T7。9MDSCTTregIL-10TGF-β。10CCL2MDSCCCR2CCR2MDSCCCL2/CCR2。MDSCMDSC。100RudolphVir-chow。inflammation。“smoldering”。MDSCTreg。TregTregTregMDSClipoxinA411。“”12。TregMDSC。Treg·211·．Treg。123Treg。2。、。13。、5-、、14-15。DC、T、B16。17CD4+CD25+T。。。18stemcellfactorSCFSCFc-kitMMP-9SCFSCF。IL-6、TNF-α、VEGF、Cox-2、iNOS、CCL2TNK。19CCL2MDSC。MDSCIL-17CCL17CCL22Treg。TregCD39CD73TregIL-9。。3TollToll-likereceptorTLR。TLRⅠpatternrecognitionreceptorPRRpathogenassociatedmolec-ularpatternPAMP20。TLR。200521TLRTLR4TLR3TLRs。22TLR、。Toll。TLR、HMGB1、HSP、RNA/DNA、23。Toll。TollmicroparticleMP。100～1000nm24-26。、、27。Toll·311·20124192。RNAmicroRNAmicroRNAlet-7bIL-6。TLR。4。、、。。、pH。。。。。anchoragedependent。、、。integrin、、28-29。、。5。MDSCTreg。Toll。。1HanahanDWeinbergRA．ThehallmarksofcancerJ．Cell2000100157-70．2HanahanDWeinbergRA．HallmarksofcancerThenextgener-ationJ．Cell20111445646-674．3BrownJM．TumormicroenvironmentandtheresponsetoanticancertherapyJ．CancerBiolTher200215453-458．4LawrenceT．InflammationandcancerAfailureofresolutionJ．TrendsPharmacolSci2007284162-165．5BalkwillFCharlesKAMantovaniA．SmolderingandpolarizedinflammationintheinitiationandpromotionofmalignantdiseaseJ．CancerCell200573211-217．6DunnGPOldLJSchreiberRD．ThethreeEsofcancerimmu-noeditingJ．AnnuRevImmunol200422329-360．7GabrilovichDNagarajS．Myeloid-derivedsuppressorcellsasreg-ulatorsoftheimmunesystemJ．NatRevImmunol200993162-174．8YangLDeBuskLMFukudaKetal．Expansionofmyeloidim-munesuppressorGr+CD11b+cellsintumor-bearinghostdirectlypromotestumorangiogenesisJ．CancerCell200464409-421．9HuangBPanPLiQetal．Gr-1+CD115+immaturemyeloidsuppressorcellsmediatethedevelopmentoftumor-inducedTregu-latorycellsandT-cellanergyintumor-bearinghostJ．CancerRes20066621123-1131．10HuangBLeiZZhaoJetal．CCL2/CCR2pathwaymediatesre-cruitmentofmyeloidsuppressorcellstocancersJ．CancerLett2007252186-92．11ZhangBJiaHLiuJetal．DepletionofregulatoryTcellsfacili-tatesgrowthofestablishedtumorsAmechanisminvolvingthereg-ulationofmyeloid-derivedsuppressorcellsbylipoxinA4J．JImmunol2010185127199-7206．·411·．12BradyHRSerhanCN．LipoxinsPutativebrakingsignalsinhostdefenseinflamemationandhypersensitivityJ．CurrOpinNeph-rolHypertens19965120-27．13TheoharidesTCKalogeromitrosD．ThecriticalroleofmastcellsinallergyandinflammationJ．AnnNYAcadSci2006108878-99．14KinetJP．Theessentialroleofmastcellsinorchestratinginflamma-tionJ．ImmunolRev20072175-7．15MetzMGrimbaldestonMANakaeSetal．Mastcellsinthepro-motionandlimitationofchronicinflammationJ．ImmunolRev2007217304-328．16GalliSJNakaeSTsaiM．Mastcellsinthedevelopmentofadap-tiveimmuneresponsesJ．NatImmunol200562135-142．17LuLFLindEFGondekDCetal．Mastcellsareessentialinter-mediariesinregulatoryT-celltoleranceJ．Nature20064427106997-1002．18HuangBLeiZZhang