Tubeimoside-1 induces TFEB-dependent lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting mTOR  

作　　者：Xiaojia Liu Mingxiao Yin Jingwen Dong Genxiang Mao Wenjian Min Zean Kuang Peng Yang Lu Liu Na Zhang Hongbin Deng 

机构地区：[1]Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China [2]Zhejiang Provincial Key Lab of Geriatrics,Department of Geriatrics,Zhejiang Hospital,Hangzhou 310013,China [3]State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization,China Pharmaceutical University,Nanjing 210009,China [4]Qingdao Women and Children’s Hospital,Qingdao University,Qingdao 266034,China

出　　处：《Acta Pharmaceutica Sinica B》2021年第10期3134-3149,共16页药学学报（英文版）

基　　金：supported by grants from National Natural Science Foundation of China(81973366,81773782,81903695 and 82003792);CAMS Innovation Fund for Medical Sciences(2016I2M-1-011,China);National Mega-project for Innovative Drugs(2019ZX09721-001,China);Chinese Pharmaceutical Association-Yiling Pharmaceutical Innovation Fund for Biomedicine(GL-1-B04-20180366,China)。

摘　　要：Programmed cell death ligand 1(PD-L1)/programmed cell death protein 1(PD-1)cascade is an effective therapeutic target for immune checkpoint blockade(ICB)therapy.Targeting PD-L1/PD-1 axis by small-molecule drug is an attractive approach to enhance antitumor immunity.Using flow cytometry-based assay,we identify tubeimoside-1(TBM-1)as a promising antitumor immune modulator that negatively regulates PD-L1 level.TBM-1 disrupts PD-1/PD-L1 interaction and enhances the cytotoxicity of T cells toward cancer cells through decreasing the abundance of PD-L1.Furthermore,TBM-1 exerts its antitumor effect in mice bearing Lewis lung carcinoma(LLC)and B16 melanoma tumor xenograft via activating tumor-infiltrating T-cell immunity.Mechanistically,TBM-1 triggers PD-L1 lysosomal degradation in a TFEB-dependent,autophagy-independent pathway.TBM-1 selectively binds to the mammalian target of rapamycin(m TOR)kinase and suppresses the activation of m TORC1,leading to the nuclear translocation of TFEB and lysosome biogenesis.Moreover,the combination of TBM-1 and anti-CTLA-4 effectively enhances antitumor T-cell immunity and reduces immunosuppressive infiltration of myeloid-derived suppressor cells(MDSCs)and regulatory T(Treg)cells.Our findings reveal a previously unrecognized antitumor mechanism of TBM-1 and represent an alternative ICB therapeutic strategy to enhance the efficacy of cancer immunotherapy.

关 键 词：PD-L1 Immune checkpoint blockade Transcription factor EB LYSOSOME MTOR 

分 类 号：R730.51[医药卫生—肿瘤]