SCI
18July
ResistancetodurvalumabanddurvalumabplustremelimumabisassociatedwithfunctionalSTK11mutationsinnon-small-celllungcancerpatientsandisreversedbySTAT3knockdown
(CancerDiscovery;IF:39.39)
PoreN,WuS,StandiferN,etal.ResistancetodurvalumabanddurvalumabplustremelimumabisassociatedwithfunctionalSTK11mutationsinnon-small-celllungcancerpatientsandisreversedbySTAT3knockdown.CancerDiscov
CORRESPONDENCETO:CorrespondingauthorsMariaAscierto,PhDandMichaelOberst,PhDAstraZenecaOneMedImmuneWayGaithersburg,MD,USAPhone:--(MLA);--(MDO)
ABSTRACT摘要MutationsintheSTK11(LKB1)generegulateresistancetoPD-1/PD-L1blockade.Thisstudyevaluatedthisassociationinpatientswithnonsquamousnon-small-celllungcancerenrolledinthreePhase1/2trials.STK11mutationswereassociatedwithresistancetotheanti-PD-L1antibodydurvalumab(alone/withtheanti-CTLA-4antibodytremelimumab)independentlyofKRASmutationalstatus,highlightingSTK11asapotentialdriverofresistancetocheckpointblockade.Retrospectiveassessmentsoftumortissue,wholebloodandserumrevealedauniqueimmunephenotypeinpatientswithSTK11mutations,withincreasedexpressionofmarkersassociatedwithneutrophils(i.e.CXCL2,IL6),Th17contexture(i.e.IL17A)andimmunecheckpoints.Associatedchangeswereobservedintheperiphery.ReductionofSTAT3inthetumormicroenvironmentusinganantisenseoligonucleotidereversedimmunotherapyresistanceinpreclinicalSTK11knockoutmodels.TheseresultssuggestthatSTK11mutationsmayhinderresponsetocheckpointblockadethroughmechanismsincludingsuppressivemyeloidcellbiology,whichcouldbereversedbySTAT3-targetedtherapy.
STK11(LKB1)基因突变调节对PD-1/PD-L1阻滞剂的耐药性。这项研究评估了参加三期1/2试验的非鳞状非小细胞肺癌患者的这种相关性。STK11突变与抗PD-L1抗体度伐利尤单抗(单独/与抗CTLA-4抗体替昔木单抗)的耐药性相关，与KRAS突变状态无关，突出了STK11是抵抗检查点封锁的潜在驱动因素。对肿瘤组织、全血和血清的回顾性分析显示，STK11突变患者具有独特的免疫表型，与中性粒细胞(即CXCL2、IL6)、Th17结构(即IL17A)和免疫检查点相关的标志物表达增加。在外周也观察到相关的变化。在临床前STK11基因敲除模型中使用反义寡核苷酸降低肿瘤微环境中的STAT3可以逆转免疫治疗耐药性。这些结果表明，STK11突变可能通过抑制髓系细胞生物学等机制阻碍对检查点封锁的反应，这种机制可以被STAT3靶向治疗逆转。
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