Innateimmunesignalingandregulationincancerimmunotherapy
ReviewCellResearch()
Apre-existingTcell-inflamedtumormicroenvironmenthasprognosticutilityandalsocanbepredictiveforresponsetocontemporarycancerimmunotherapies.ThegenerationofaspontaneousTcellresponseagainsttumor-associatedantigensdependsoninnateimmuneactivation,whichdrivestypeIinterferon(IFN)production.
RecentworkhasrevealedamajorrolefortheSTINGpathwayofcytosolicDNAsensinginthisprocess.ThiscascadeofeventscontributestotheactivationofBatf3-lineagedendriticcells(DCs),whichappeartobecentraltoanti-tumorimmunity.Non-Tcell-inflamedtumorslackchemokinesforBatf3DCrecruitment,havefewBatf3DCs,andlackatypeIIFNgenesignature,suggestingthatfailedinnateimmuneactivationmaybetheultimatecauseforlackofspontaneousTcellactivationandaccumulation.Withthisinformationinhand,newstrategiesfortriggeringinnateimmuneactivationandBatf3DCrecruitmentarebeingdeveloped,includingnovelSTINGagonistsfordenovoimmunepriming.Ultimately,thesuccessfuldevelopmentofeffectiveinnateimmuneactivatorsshouldexpandthefractionofpatientsthatcanrespondtoimmunotherapies,suchaswithcheckpointblockadeantibodies.
目前存在的T细胞炎症肿瘤微环境在预防治疗方面具有价值，也可以作为目前肿瘤免疫疗法反应的预测。T细胞对肿瘤相关抗原的自然反应取决于先天免疫活化和I型干扰素（IFN）的生成。
最近的研究发现胞浆DNA传感相关的STING通路的重要作用。这一连串的事件导致Batf3依赖树突状细胞（DC）的活化，与抗肿瘤免疫的核心相关联。非T细胞性肿瘤缺乏趋化因子，无法有效募集Batf3DC，缺乏I型IFN，表明先天免疫激活的失败可能是导致先天性T细胞的激活缺失和数量缺少的根本原因。基于这些研究信息，许多正在进行的研究专注于先天免疫激活和Batf3DC募集的策略，包括新型STING通路激动剂，有效启动免疫通路。最终，有效的天然免疫激活剂的成功研发，需要扩大对免疫疗法具有反应的患者数量，免疫疗法例如检查点阻断抗体。
Figure1AcentralroleofBatf3DCsandtheSTINGpathwayinorchestratinganti-tumorTcellresponses.
TumorcellsdisplayingaTcell-inflamedphenotypeproducechemokines,suchasCCL4,whichrecruitBatf3DCs.CytosolicDNAinAPCsactivatestheSTINGpathway,resultinginthesecretionoftypeIIFNsandalsoofthechemokinesCXCL9andCXCL10.TumorendothelialcellscanalsocontributetotheproductionoftypeIIFNs.Thiscytokinesubsequentlyfacilitatestheactivationoftumor-infiltratingBatf3DCs,whichtakeuptumor-associatedantigensandmigrateviathelymphaticstothetumor-draininglymphnode,wheretheycross-primetumor-specificCD8+Tcells.TheactivatedCD8+Tcellsundergoclonalexpansioninthetumor-draininglymphnodeandtrafficviathebloodstream.TheyarerecruitedbacktothetumormicroenvironmentundertheinfluenceofCXCL9andCXCL10alsoreleasedbyBatf3DCsinthetumormicroenvironment.DynamicmovementofinfiltratedCD8+effectorTcellsresultsindirectcontactwithtumorcells,whichcanleadtotumorcelldeath.Iftumorcellsarenot鍖椾含娌荤枟鐧界櫆椋庡摢闂村尰闄㈡渶鏉冨▉娌荤枟鐧界櫆椋庡ソ鐨勫尰鐢?
