Lettershttps://doi.org/10.1038/s41591-018-0045-31BIOPIC,BeijingAdvancedInnovationCentreforGenomics,andSchoolofLifeSciences,PekingUniversity,Beijing,China.2Peking-TsinghuaCentreforLifeSciences,AcademyforAdvancedInterdisciplinaryStudies,PekingUniversity,Beijing,China.3DepartmentofThoracicSurgery,PekingUniversityThirdHospital,Beijing,China.4PekingUniversityCancerHospital&Institute,Beijing,China.5BayerAG,Berlin,Germany.6Theseauthorscontributedequally:XinyiGuo,YuanyuanZhang,LiangtaoZheng,ChunhongZheng,JintaoSong.*e-mail:yts8966@163.com;zemin@pku.edu.cnCancerimmunotherapieshaveshownsustainedclinicalresponsesintreatingnon-small-celllungcancer1–3,buteffi-cacyvariesanddependsinpartontheamountandpropertiesoftumorinfiltratinglymphocytes4–6.Todepictthebaselinelandscapeofthecomposition,lineageandfunctionalstatesoftumorinfiltratinglymphocytes,hereweperformeddeepsingle-cellRNAsequencingfor12,346Tcellsfrom14treat-ment-naïvenon-small-celllungcancerpatients.CombinedexpressionandTcellantigenreceptorbasedlineagetrack-ingrevealedasignificantproportionofinter-tissueeffectorTcellswithahighlymigratorynature.Aswellastumor-infil-tratingCD8+Tcellsundergoingexhaustion,weobservedtwoclustersofcellsexhibitingstatesprecedingexhaustion,andahighratioof“pre-exhausted”toexhaustedTcellswasassociatedwithbetterprognosisoflungadenocarcinoma.Additionally,weobservedfurtherheterogeneitywithinthetumorregulatoryTcells(Tregs),characterizedbythebimodaldistributionofTNFRSF9,anactivationmarkerforantigen-specificTregs.ThegenesignatureofthoseactivatedtumorTregs,whichincludedIL1R2,correlatedwithpoorprognosisinlungadenocarcinoma.OurstudyprovidesanewapproachforpatientstratificationandwillhelpfurtherunderstandthefunctionalstatesanddynamicsofTcellsinlungcancer.Non-small-celllungcancer(NSCLC)istheleadingcauseofcancer-relatedmortalityandaccountsfor~85%oflungcancers7.NSCLCtumorstypicallyharborextensivegenomicalterations8,withhighmutationloadlinkingtobetterresponsetocheckpointblock-ade5althoughwithexceptions9.Toshedl...
