Pan-Bcl-2 Inhibitor AT-101 Enhances Tumor Cell Killing by EGFR Targeted T Cells 英文参考文献.docVIP

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Pan-Bcl-2 Inhibitor AT-101 Enhances Tumor Cell Killing by EGFR Targeted T Cells 英文参考文献.doc

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Pan-Bcl-2 Inhibitor AT-101 Enhances Tumor Cell Killing by EGFR Targeted T Cells 英文参考文献

Pan-Bcl-2InhibitorAT-101EnhancesTumorCellKilling byEGFRTargetedTCells ArchanaThakur1*,LawrenceG.Lum1,3,DanaSchalk1,AsfarAzmi2,SanjeevBanerjee2,FazlulH.Sarkar2, RamziMohommad2 1DepartmentsofOncologyandMedicine,KarmanosCancerInstitute,WayneStateUniversity,Detroit,Michigan,UnitedStatesofAmerica,2DepartmentofPathology, KarmanosCancerInstitute,WayneStateUniversity,Detroit,Michigan,UnitedStatesofAmerica,3ImmunologyandMicrobiology,KarmanosCancerInstitute,WayneState University,Detroit,Michigan,UnitedStatesofAmerica Abstract Pancreaticcancerisadeadlydiseaseandhastheworstprognosisamongalmostallcancersandisindireneedofnewand improvedtherapeuticstrategies.Conditioningoftumorcellswithchemotherapeuticdrughasbeenshowntoenhancethe anti-tumor effects of cancer vaccines and adoptive cell therapy. In this study, we investigated the immunomodulatory effectsofpan-Bcl-2inhibitorAT-101onpancreaticcancer(PC)cellcytotoxicitybyactivatedTcells(ATC).TheeffectsofAT- 101 on cytotoxicity, early apoptosis, and Granzyme B (GrzB) and IFN-c signaling pathways were evaluated during EGFR bispecific antibody armed ATC (aATC)-mediated killing of L3.6pl and MiaPaCa-2 PC cells pre-sensitized with AT-101. We foundthatpretreatmentoftumorcellswithAT-101enhancedsusceptibilityofL3.6plandMiaPaCa-2tumorcellstoATCand aATC-mediatedcytotoxicity,whichwasinpartmediatedviaenhancedreleaseofcytolyticgranuleGrzBfromATCandaATC. AT-101-sensitized L3.6pl cells showed up-regulation of IFN-c-mediated induction in the phosphorylation of Ser727-Stat1 (pS727-Stat1),andIFN-cinduceddephosphorylationofphospho-Tyr705-Stat3(pY705-Stat3).Priming(conditioning)ofPCcells with AT-101 can significantly enhance the anti-tumor activity of EGFRBi armed ATC through increased IFN-c induced activationofpS727-Stat1andinhibitionofpY705-Stat3phosphorylation,andresultinginincreasedratioofpro-apoptoticto anti-apoptoticproteins.Ourresultsverifyenhancedcytotoxicityafteranovelchemotherapyconditioningstrategyagainst PCthatwarrantsfurtherinvivoandclinic