Although chemotherapy and recently approved immunotherapies have improved treatment of triple-negative breast cancer(TNBC),the clinical outcome for this deadly disease remains unsatisfactory.We found that both cluster of differentiation 73(CD73)and transforming growth factor(TGF)β were elevated in TNBC and correlated with the epithelial-mesenchymal transition(EMT),fibrotic stroma,an immune-tolerant tumor environment,and poor prognosis.To explore the efficacy of CD73-TGFβ dual-blockade,we generated a bifunctional anti-CD73-TGFβ construct consisting of the CD73 antibody MEDI9447 fused with the TGFβRII extracellular-domain(termed MEDI-TGFβR).MEDI-TGFβR retained full and simultaneous blocking efficiency for CD73 and TGFβ.Compared with MEDI9447 activity alone,MEDI-TGFβR demonstrated superior inhibitory activity against CD73-dependent cell migration and the EMT in CD73-high TNBC cells and effectively reduced lung metastasis in a syngeneic mouse model of TNBC.Mechanistically,the CD73-TGFβ dual-blockade reverted the EMT and stromal fibrosis and induced tumor cell death,which was accompanied by the accumulation of M1-macrophages and production of tumor necrosis factor α(TNFα).The CD73-TGFβ dual-blockade promoted a multifaceted inflammatory tumor microenvironment,as shown by the diminished levels of myeloid-derived suppressor cells(MDSCs)and M2-macrophages,and substantially increased levels of activated dendritic cells,cytotoxic T cells,and B cells.Collectively,our results have highlighted a novel strategy for TNBC treatment.

Yun Xing;Zhi-qiang Ren;Rui Jin;Liang Liu;Jin-peng Pei;Ker Yu

Department of Pharmacology,Fudan University School of Pharmacy,Shanghai 201203,China

中国药理学报（英文版）

[1]Yun Xing;Zhi-qiang Ren;Rui Jin;Liang Liu;Jin-peng Pei;Ker Yu-.Therapeutic efficacy and mechanism of CD73-TGFβdual-blockade in a mouse model of triple-negative breast cancer)[J].中国药理学报（英文版）,2022(09):2410-2418

MEDI9447,MEDI,syngeneic

Therapeutic,efficacy,mechanism,CD73,TGF,dual,blockade,mouse,model,triple,negative,breast,cancer,Although,chemotherapy,recently,approved,immunotherapies,have,improved,treatment,TNBC,clinical,outcome,this,deadly,disease,remains,unsatisfactory,We,found,that,both,cluster,differentiation,transforming,growth,were,elevated,correlated,epithelial,mesenchymal,transition,EMT,fibrotic,immune,tolerant,tumor,poor,prognosis,To,explore,generated,bifunctional,construct,consisting,antibody,fused,RII,extracellular,domain,termed,retained,full,simultaneous,blocking,efficiency,Compared,activity,alone,demonstrated,superior,inhibitory,against,dependent,migration,cells,effectively,reduced,lung,metastasis,Mechanistically,reverted,stromal,fibrosis,induced,death,which,was,accompanied,by,accumulation,M1,macrophages,production,necrosis,promoted,multifaceted,inflammatory,microenvironment,shown,diminished,levels,myeloid,derived,suppressor,MDSCs,M2,substantially,increased,activated,dendritic,cytotoxic,Collectively,our,results,highlighted,novel,strategy

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