25may2017神奇的大蛇丸2017/07/10WhetherthereisPD-1expressiononTAMs？WherePD-1+TAMscomefrom?what’sthephenotypeofPD-1+TAMs?what’sthefunctionofPD-1expressedonTAMS?Howaboutthecombinationofanti-PD-1withanti-CD47?SCANRobertHVonderheide.naturemedicine.2015Topicsentence：whethermacrophagesmightalsoexpressPD-1inthetumourmicroenvironment,andifso,whatconsequencesPD-1expressionmighthaveonanti-tumourimmunity.BackgroundFACSofdissociatedtumoursthreeweeksafterengraftmentintomiceshowedthatahighpercentageofmacrophagesinthetumourexpressedsurfacePD-1.(tissuesite？)Arlauckasetal.,Sci.Transl.Med.2017RESULTsM1(CD206−MHCIIhigh)M2(CD206+MHCIIlowornegative)almostallPD-1+TAMsexpressedanM2-likesurfaceprofile,whereasPD-1−TAMsshowedatrendtowardstheexpressionofanM1-likeprofilePD-1⁺PD-1⁻PD-1+TAMpopulationisnotstatic;itbeginstoemergeabout2weeksafterengraftment,andincreasesovertimethefrequencyofPD-1+TAMsincreasedwithdiseasestage,aswellaswithtumourvolumeinmicemodels.(amarkerforM2?)WherePD-1+TAMscomefrom?组织损伤修复————炎症巨噬细胞SubhraK.B.&AlbertoM.natureimmunology.2010问题：1、肿瘤的进展或许是因为组织修复能力的缺失，是Treg、TAMs等调节细胞类群功能的阻滞2、如果是这样，那么将具有正常组织修复能力的细胞类群赋予肿瘤组织或许能够建立正常的组织修复JingWang&PaulKubes.cell.2016bonemarrowtransplantationexperimentsuggeststhatthemajorityofPD-1+TAMsandTILsoriginatefromcirculatingleukocytes,ratherthanfromresidentimmunecells.6wMC383wFACSFACSmyeloid(CD11b+)granulocyte(Gr1high)Tcell(TCRβ+)Bcell(CD19+)what’sthephenotypeofPD-1+TAMs？PD-1+TAMsappearedlargeand‘foamy’incontrasttoPD-1−TAMs,whichweresmallerandmoremonocyticinappearance“PD-1positive”meanswhat？Activation？Exhaustion？Orelse？JI.2003what’sthefunctionofPD-1expressedonTAMS?anexvivophagocytosisassaywithGFP+Staphylococcusaureus(金葡菌)bioparticlesSo,thePD-1+TAMshaveareducedcapacityforphagocytosisCT-26PD-1+TAMsPD-1−TAMsS.AureusphagocytosisSubhraK.B.&AlbertoM.natureimmunology.2010UseNOD&NSGmicetofurtherinvestigatethisinhibitioninvivoThesemodelssharethesamepatternofPD-1expressiononTAMs.PD-L1over-expressingYFP+CT26PD-L1knockoutYFP+CT26tFACSPD-L1over-expressingYFP+CT26PD-L1knockoutYFP+CT26ThedecreaseintumourburdenandincreaseinPD-1+TAMphagocytosisuponPD-L1removalsuggeststhatthePD-1–PD-L1pathwayspecificallyinhibitsTAMfunction.So，thePD-1–PD-L1interactionblockademayenhanceTAManti-tumourimmunityPD-L1-GFP-luc-DLD-1BLIanti-mousePD-1antibodyHAC,anengineered,smallproteinwithhumanPD-L1-blockingactivityTAMdepletionwithanti-CSF1RTHISdemonstratethatspecificinhibitionofthePD-1–PD-L1axisinTAMsisresponsiblefortheanti-tumourefficacyHowaboutthecombinationofanti-PD-1withanti-CD47?SummaryThisarticlesuggeststhatPD-1expressionisaglobalmechanismforlimitingimmunityacrosstheinnateandadaptiveimmunesystem.So,thereismoreextensivemeaningforanti-PD-1oranti-PD-L1therapies.
