Inhibition of MYC suppresses programmed cell death ligand-1 expression and enhances immunotherapy in triple-negative breast cancer  

作　　者：Xintong Li Lin Tang Qin Chen Xumin Cheng Yiqiu Liu Cenzhu Wang Chengjun Zhu Kun Xu Fangyan Gao Jinyi Huang Runtian Wang Xiaoxiang Guan 

机构地区：[1]Department of Oncology,The First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu 210029,China [2]Medical School of Nanjing University,Nanjing,Jiangsu 210093,China [3]Department of Breast Surgery,The First Affiliated Hospital with Nanjing Medical University,Nanjing,Jiangsu 210029,China [4]Jiangsu Key Lab of Cancer Biomarkers,Prevention and Treatment,Collaborative Innovation Center for Personalized Cancer Medicine,Nanjing Medical University,Nanjing,Jiangsu 210029,China

出　　处：《Chinese Medical Journal》2022年第20期2436-2445,共10页中华医学杂志（英文版）

基　　金：Key International Cooperation of the National Natural Science Foundation of China(No. 81920108029);Key Foundation for Social Development Project of the Jiangsu Province, China(No. BE2021741)

摘　　要：Background:Cancer immunotherapy has emerged as a promising strategy against triple-negative breast cancer(TNBC).One of the immunosuppressive pathways involves programmed cell death-1(PD-1)and programmed cell death ligand-1(PD-L1),but many patients derived little benefit from PD-1/PD-L1 checkpoint blockades treatment.Prior research has shown that MYC,a master transcription amplifier highly expressed in TNBC cells,can regulate the tumor immune microenvironment and constrain the efficacy of immunotherapy.This study aims to investigate the regulatory relationship between MYC and PD-L1,and whether a cyclin-dependent kinase(CDK)inhibitor that inhibits MYC expression in combination with anti-PD-L1 antibodies can enhance the response to immunotherapy.Methods:Public databases and TNBC tissue microarrays were used to study the correlation between MYC and PD-L1.The expression of MYC and PD-L1 in TNBCs was examined by quantitative real-time polymerase chain reaction and Western blotting.A patient-derived tumor xenograft(PDTX)model was used to evaluate the influence of a CDK7 inhibitor THZ1 on PD-L1 expression.Cell proliferation and migration were detected by 5-ethynyl-2′-deoxyuridine(EdU)cell proliferation and cell migration assays.Tumor xenograft models were established for in vivo verification.Results:A high MYC expression level was associated with a poor prognosis and could alter the proportion of tumor-infiltrating immune cells(TIICs).The positive correlation between MYC and PD-L1 was confirmed by immunostaining samples from 165 TNBC patients.Suppression of MYC in TNBC caused a reduction in the levels of both PD-L1 messenger RNA and protein.In addition,antitumor immune response was enhanced in the TNBC cancer xenograft mouse model with suppression of MYC by CDK7 inhibitor THZ1.Conclusions:The combined therapy of CDK7 inhibitor THZ1 and anti-PD-L1 antibody appeared to have a synergistic effect,which might offer new insight for enhancing immunotherapy in TNBC.

关 键 词：Triple negative breast neoplasms MYC Programmed cell death ligand 1 PD-L1 CDK7 THZ1 IMMUNOTHERAPY 

分 类 号：R737.9[医药卫生—肿瘤]