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Notch signaling inhibitor and anti-pd-l1 antibody combination therapies decelerate tumor progression in pancreatic cancer

引用

Journal of Pancreatology 2021年第2期4卷 106-114页

作者： Hongmei Dai Xiafei Hong Dan Huang Huanwen Wu Xianze Wang Hao Chen Rui Jiang Wenyan Chen Yupei Zhao Wenming Wu Department of General Surgery School of MedicineTsinghua UniversityBeijingChina Medical Research Center School of MedicineTsinghua UniversityBeijingChina Department of Pathology Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeSchool of MedicineTsinghua UniversityBeijingChina Department of Basic Medical Sciences School of MedicineTsinghua UniversityBeijingChina

Objective:Pancreatic cancer(PC)is a highly lethal malignancy with an immunosuppressive ***,current immune checkpoint inhibitor monotherapies have shown limited efficacy in PC,prompting the need for combination ***,we hypothesized that combinations of Notch signaling inhibitor and anti-ligand programmed death-ligand 1(pd-l1)antibody immunotherapy would show synergistic ***:The baseline expression of pd-l1 and HES1 was measured in PC cell lines,single-cell RNA-seq data of PC(GSA:CRA001160),and cBioPortal *** an in vitro study,MIA PaCa2 and SW1990 were used to explore the mechanism between Notch signaling and *** study the effects in vivo,a subcutaneous tumor model was established using Pan02 cells treated with either anti-pd-l1 monoclonal antibody and/or Notch inhibitor *** study performed involving human samples was approved by the Ethics Committee of Peking Union Medical College Hospital(approval No.S-K460,approval date:April 23,2018).Animal studies were approved by the Animal Research Ethics Committee of Peking Union Medical College Hospital(approval ***-2019-049,approval date:November 28,2019).Results:The Notch signaling inhibitor upregulated pd-l1 expression in PC tumor cells both in vitro and in *** effector HES1 knockdown produced pd-l1 upregulation in both MIA PaCa2 and SW1990 *** DAPT and anti-pd-l1 antibody treatment of Pan02 subcutaneous tumor model resulted in significantly reduced tumor weights compared to that with monotherapy,as well as significantly reduced Ki67 than that in the monotherapy group and control *** cytometry analysis revealed significantly increased CD8+T cell infiltration in tumors of the combination group compared with those of the monotherapy ***:Notch signaling blockade might enhance the antitumor effect of anti-pd-l1 therapy in PC.

关键词： DAPT Notch signaling blockade Pancreatic cancer pd-l1 immune checkpoint pd-l1 upregulation

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