PD-L1 is a direct target of cancer-FOXP3 in pancreatic ductal adenocarcinoma(PDAC),and combined immunotherapy with antibodies against PD-L1 and CCL5 is effective in the treatment of PDAC

查看全文 作　　者：Xiuchao [1,2,3]Wang;Xin [1,3]Li;Xunbin [4]Wei;Haiping [1]Jiang;Chungen [1]Lan;Shengyu [2]Yang;Han [5]Wang;Yanhui [6]Yang;Caijuan [7]Tian;Zanmei [7]Xu;Jiangyan [7]Zhang;Jihui [3]Hao;He [1,3]Ren

机构地区：[1]Department of Gastroenterology,Center of Tumor Immunology and Cytotherapy,The Affiliated Hospital of Qingdao University,266003 Qingdao,China;[2]Department of Cellular and Molecular Physiology,Penn State College of Medicine,Hershey,PA 17033,USA;[3]Department of Pancreatic Cancer,Tianjin Medical University Cancer Institute and Hospital,300060 Tianjin,China;[4]Department of Geriatric Dentistry,Beijing Laboratory of Biomedical Materials,Peking University School and Hospital of Stomatology,and Biomedical Engineering Department,Peking University,100081 Beijing,China;[5]Department of Applied Statistics,College of Science,Hebei University of Technology,300401 Tianjin,China;[6]NHC Key Laboratory of Hormones and Development(Tianjin Medical University),Tianjin Key Laboratory of Metabolic Diseases,Tianjin Medical University Chu Hsien-I Memorial Hospital&Tianjin Institute of Endocrinology,300134 Tianjin,China;[7]Tianjin Marvel Medical Laboratory,Tianjin Marvelbio Technology Co.,Ltd,300381 Tianjin,China

出　　处：《Signal Transduction and Targeted Therapy》索引2020年第5卷第1期,共12页

基　　金：funded by The National Natural Science Foundation of China(NSFC,under award numbers 81772633,81672431,81700631,61425006);the Taishan Scholars Program of Shandong Province,and the SJTU Medicine Engineering Interdisciplinary Research Fund under award number YG2017MS19. 摘　　要：High expression of PD-L1 marks the poor prognosis of pancreatic ductal adenocarcinomas(PDAC).However,the regulatory mechanism of PD-L1 remains elusive.We recently reported that cancer Forkhead box protein 3(Cancer-FOXP3 or C-FOXP3)promoted immune evasion of PDAC by recruiting Treg cells into PDAC via upregulation of CCL5.In this study,we confirmed that PD-L1 was overexpressed in PDAC samples from two independent cohorts of patients with radical resection.Moreover,C-FOXP3 was colocalized and correlated with the expression of PD-L1 in tumor cells at the mRNA and protein levels,and this finding was confirmed by the The Cancer Genome Atlas(TCGA)database.Chromatin immunoprecipitation(ChIP)revealed that C-FOXP3 directly bound to the promoter region of PD-L1 in pancreatic cancer cells.Furthermore,overexpression of C-FOXP3 activated the luciferase reporter gene under the control of the PD-L1 promoter.However,mutation of the binding motif-a completely reversed the luciferase activity.In addition,C-FOXP3-induced upregulation of PD-L1 effectively inhibited the activity of CD8+T cells.Based on our recent finding that the CCL-5 antibody achieved a better response to PDAC models with high C-FOXP3 levels,we further demonstrated that the PD-L1 antibody strengthened the antitumor effect of CCL-5 blockade in xenograft and orthotopic mouse models with high C-FOXP3 levels.In conclusion,C-FOXP3 directly activates PD-L1 and represents a core transcription factor that mediates the immune escape of PDAC.Combined blockade of PD-L1 and CCL-5 may provide an effective therapy for patients with PDAC that have high C-FOXP3 levels. 关键词：CCL5 FOXP3 ADENOCARCINOMA

相关文献

参考文献（32）
引证文献（21）
耦合文献（14）

参考文献(32)

引证文献(21)

耦合文献(14)

互联网出版许可证新出网证(渝)字10号全国400电话 - 免长途话费

PD-L1 is a direct target of cancer-FOXP3 in pancreatic ductal adenocarcinoma(PDAC),and combined immunotherapy with antibodies against PD-L1 and CCL5 is effective in the treatment of PDAC

参考文献(32)

引证文献(21)

耦合文献(14)

用户提示