EGFR-TKI耐药后AKT/Ets1调控PD-L1的表达介导非小细胞肺癌免疫逃逸的机制探究

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[关键词]非小细胞肺癌;奥希替尼;蛋白激酶B;E26转化特异性转录因子1;程序化死亡配体1[中图分类号]R734.2 [文献标志码]A [DOI]10.19767/j.cnki.32-1412.2025.06.002

Exploring the mechanism by which AKT/Ets1 regulates PD-L1 expression to mediate immune escape in non-small cell lung cancer after EGFR-TKI resistance

MIAOJiefei，LIMei （Department of Oncology，Affiliated Hospital of Nantong University， Jiangsu 226001）

[Abstract]Objective： To explore the efficacyof immunotherapy in patients with non-smallcellung cancer （NSCLC） whoseepidermal growth factor receptor（EGFR）driver genemutations areresistant to the EGFR tyrosine kinase inhibitor （TKI）osimertinib，andthe molecularmechanismunderlying theupregulationof programmedcelldeath ligand1（PD-L1） expresion.Methods：Theeficacy of combinationimmunotherapyin NSCLC patients withacquiredresistanceto osimertinibwas analyzed retrospectively. The osimertinib-resistant cell lines PC9 ∘- OR and HCC827-OR were established，and their resistance was validated via MTTandcolony formationassays.WesternBlot experiment wasemployed to test the expressionof Ets1andPD-L1protein in drug-resistantcels.Indrug-resistantcells，AKTinhibitors（Dactolisiband LY294002）wereused toevaluatetheregulatoryefectof theAKTpathwayontheexpressionofEts1andPD-Llexpression.Analyze theefectof siRNA-mediated inhibitionofEts1expressioncombined withtheAKTinhibitor（LY294002）on the expressionofPD-L1.The expressionchangesofEts1andPD-L1inthe paraffin-embedded tissuesof patients before andafterosimertinib resistance weredetectedbyimmunohistochemical method.Results：Immunotherapycombination treatmentsignificantlyprolongedprogression-freesurvivalinNSCLC patientswith osimertinibresistance.PC9-ORandHCC827-OR cels exhibited resistance to osimertinib，and the AKT pathway was activated accompanied by the upregulationofEtslandPD-Llexpression.Theexpressionof EtsandPD-L1inparaffn-embedded tissues increasedafterdrug resistancein patients.Conclusion：Osimertinibresistanceleads totheAKTpathwayactivation，promoting theupregulation ofEtslexpresion，whichintudivesaincreaseinPD-Llexpression，andeancingtheeicacyofimmunoapyfor patients and providing a theoretical basis for combined immunotherapy.

[Key words]non-smallcellung cancer; osimertinib; protein kinase B;E26 transformation-specific sequence1; programmed cell death ligand 1

肺癌是全球发病率最高的恶性肿瘤之一，其主要的病理类型为非小细胞肺癌（non-small cell lungcancer，NSCLC），大多数肺癌患者预后不良。（剩余9029字）