利用自然杀伤免疫治疗转移性小细胞肺癌J

北京皮炎主治医院 http://pf.39.net/bdfyy/bdfzd/210410/8833187.html

SCI

6June

Harnessingnaturalkillerimmunityinmetastaticsmallcelllungcancer

SarahA.Best,JonasHess,etal.Harnessingnaturalkillerimmunityinmetastaticsmallcelllungcancer.JournalofThoracicOncology；

Correspondingauthor:KateD.Sutherland,PhDAddressforcorrespondence:TheWalterandElizaHallInstituteofMedicalResearch,Parkville,Victoria,Australia,.Ph:+61-3--.E-mail:sutherland.k

Introduction简介

Smallcelllungcancer(SCLC)isthemostaggressivesubtypeoflungcancerandthoughmostpatientsinitiallyrespondtoplatinum-basedchemotherapy,resistancerapidlydevelops.Immunotherapyhaspromiseinthetreatmentoflungcancer,howeverSCLCpatientsexhibitpooroverallresponseshighlightingthenecessityforalternativeapproaches.Naturalkiller(NK)cellsareanalternativetoTcell-basedimmunotherapies,thatdonotrequiresensitizationtoantigenspresentedonthesurfaceoftumorcells.

小细胞肺癌是肺癌中最具侵犯性的亚型，尽管大多数患者最初对铂类化疗有反应，但之后耐药性会迅速增强。虽然免疫疗法在肺癌治疗中具有很大前景，但是SCLC患者表现出较差的总体反应，这强调了改变治疗方法的必要性。自然杀伤细胞（NK细胞）是T细胞免疫疗法的另一种选择，它不需要对肿瘤细胞表面抗原敏感。

Methods方法

WeinvestigatedtheimmunophenotypeofhumanSCLCtumorsbybothflowcytometryonfreshsamplesandbioinformaticanalysis.CelllinesgeneratedfrommurineSCLCweretransplantedintomicelackingkeycytotoxicimmunecells.Subcutaneoustumorgrowth,metastaticdisseminationandtheactivationofCD8+TandNKcellswereevaluatedbyhistologyandflowcytometry.

我们通过在新鲜样本上的流式细胞学和生物信息分析两种方法，来研究人类SCLC肿瘤的免疫表型。小鼠SCLC产生的细胞株被移植到缺乏关键细胞毒性免疫细胞的小鼠体内。通过组织学和流式细胞学来评估皮下肿瘤生长，转移，以及CD8+T细胞和NK细胞的活化情况。

Results结果

TranscriptomicanalysisofhumanSCLCtumorsrevealedheterogeneousimmunecheckpointandcytotoxicsignatureprofiles.Utilizingsophisticatedgeneticallyengineeredmousemodels,wedemonstratedthattheabsenceofNKcells,butnotCD8+Tcells,significantlyenhancedmetastaticdisseminationofSCLCtumorcellsinvivo.Moreover,hyperactivationofNKcellactivitythroughaugmentationofIL-15orTGF-βsignalingpathwaysamelioratedSCLCmetastases,aneffectwhichwasenhancedwhen