Blocking TLR2 Activity Attenuates Pulmonary Metastases of Tumor 英文参考文献.docVIP

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Blocking TLR2 Activity Attenuates Pulmonary Metastases of Tumor 英文参考文献.doc

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Blocking TLR2 Activity Attenuates Pulmonary Metastases of Tumor 英文参考文献

BlockingTLR2ActivityAttenuatesPulmonaryMetastases ofTumor Hong-ZhenYang1.,BingCui1.,Han-ZhiLiu1,SuMi1,JunYan1,Hui-MinYan1,FangHua1,HengLin1, Wen-FengCai1,Wen-JieXie1,Xiao-XiLv1,Xiao-XingWang1,Bing-MuXin1,Qi-MinZhan2 ,Zhuo-Wei Hu1,2 * 1Molecular Immunology and Pharmacology Laboratory, Institute of Materia Medica, Chinese Academy of Medical Sciences Peking Union Medical College, Beijing, China,2StateKeyLaboratoryofMolecularOncology,CancerInstituteandCancerHospital,ChineseAcademyofMedicalSciencesPekingUnionMedicalCollege,Beijing, China Abstract Background:Metastasisisthemostpivotalcauseofmortalityincancerpatients.Immunetoleranceplaysacrucialrolein tumorprogressionandmetastasis. Methods andFindings: Inthis study, weinvestigated thepotential roles andmechanisms ofTLR2 signaling ontumor metastasis inamousemodelofintravenously injectedB16melanomacells.MultiplesubtypesofTLRswereexpressedon B16cellsandseveralhumancancercelllines;TLR2mediatedtheinvasiveactivityofthesecells.Highmetastatic B16cells released moreheatshock protein 60thanpoormetastatic B16-F1 cells. Importantly, heatshock protein 60released by tumor cells caused apersistent activation ofTLR2 and was critical inthe constitutive activation oftranscription factor Stat3, leading to the release of immunosuppressive cytokines and chemokines. Moreover, targeting TLR2 markedly reduced pulmonary metastases and increased the survival of B16-bearing mice by reversing B16 cells induced immunosuppressive microenvironment and restoring tumor-killing cells such as CD8+ T cells and M1 macrophages. Combining ananti-TLR2 antibodyandacytotoxic agent,gemcitabine, providedafurtherimprovement inthesurvival of tumor-bearing mice. Conclusions and Significance: Our results demonstrate that TLR2 is an attractive target against metastasis and that targetingimmunosuppressivemicroenvironmentusinganti-TLR2antibodyisanoveltherapeuticstrategyforcombatinga life-threateningmetastasis. Citation:YangH-Z,CuiB,LiuH-Z,MiS,YanJ,etal.(2