Tumor‐reactive immune cells protect against metastatic tumor and induce immunoediting of indolent but not quiescent tumor cells

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: adoptive immunotherapy;    dormancy;    escape;    relapse;    breast cancer;   

DOI  :  10.1189/jlb.5A1215-580R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Twomajorbarrierstocancerimmunotherapyincludetumor‐inducedimmunesuppressionmediatedbymyeloid‐derivedsuppressorcellsandpoorimmunogenicityofthetumor‐expressingself‐antigens.Toovercomethesebarriers,wereprogrammedtumor‐immunecellcross‐talkbycombineduseofdecitabineandadoptiveimmunotherapy,containingtumor‐sensitizedTcellsandCD25+NKTcells.Decitabinefunctionedtoinducetheexpressionofhighlyimmunogeniccancertestisantigensinthetumor,whilealsoreducingthefrequencyofmyeloid‐derivedsuppressorcellsandthepresenceofCD25+NKTcellsrenderedTcells,resistanttoremainingmyeloid‐derivedsuppressorcells.Thiscombinatorialtherapysignificantlyprolongedsurvivalofanimalsbearingmetastatictumorcells.Adoptiveimmunotherapyalsoinducedtumorimmunoediting,resultingintumorescapeandassociateddisease‐relatedmortality.Toidentifyatumortargetthatisincapableofescapefromtheimmuneresponse,weuseddormanttumorcells.WeusedAdriamycinchemotherapyorradiationtherapy,whichsimultaneouslyinducetumorcelldeathandtumordormancy.ResultantdormantcellsbecamerefractorytoadditionaldosesofAdriamycinorradiationtherapy,buttheyremainedsensitivetotumor‐reactiveimmunecells.Importantly,wediscoveredthatdormanttumorcellscontainedindolentcellsthatexpressedlowlevelsofKi67andquiescentcellsthatwereKi67negative.Whereastheformerwerepronetotumorimmunoeditingandescape,thelatterdidnotdemonstrateimmunoediting.Ourresultssuggestthatimmunotherapycouldbehighlyeffectiveagainstquiescentdormanttumorcells.Thechallengeistodevelopcombinatorialtherapiesthatcouldestablishaquiescenttypeoftumordormancy,whichwouldbethebesttargetforimmunotherapy...

【 授权许可】

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