1. Tubeimoside-1 induces TFEB-dependent lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting mTOR
- Author
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Mingxiao Yin, Xiaojia Liu, Na Zhang, Genxiang Mao, Lu Liu, Hongbin Deng, Peng Yang, Wenjian Min, Kuang Ze'an, and Jingwen Dong
- Subjects
MDSCs, myeloid-derived suppressor cells ,medicine.medical_treatment ,CQ, chloroquine ,mTORC1 ,Transcription factor EB ,urologic and male genital diseases ,TFEB, nuclear transcriptional factor EB ,CETSA, cellular thermal shift assay ,0302 clinical medicine ,Cancer immunotherapy ,ICB, immune checkpoint blockade ,General Pharmacology, Toxicology and Pharmaceutics ,p70S6K, phosphorylation of p70 S6 kinase ,0303 health sciences ,biology ,Chemistry ,qRT-PCR, quantitative real-time polymerase chain reaction ,Lysosome ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,mTOR ,Original Article ,IHC, immunohistochemistry ,PD-L1 ,SPR, surface plasmon resonance ,mTOR, mammalian target of rapamycin ,RM1-950 ,PD-L1, programmed cell death ligand- 1 ,03 medical and health sciences ,CHX, cycloheximide ,NSCLC, non-small cell lung cancer ,Tregs, regulatory T-lymphocytes ,medicine ,NAG, β-N-acetylglucosaminidase ,IB, immunoblotting ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,PD-1, programmed cell death-1 ,Baf, bafilomycin A1 ,Immune checkpoint ,4EBP1, eIF4E-binding protein 1 ,TILs, tumor-infiltrating lymphocytes ,Cancer cell ,biology.protein ,Cancer research ,TFEB ,LLC, Lewis lung carcinoma ,Therapeutics. Pharmacology ,TBM-1, tubeimoside-1 ,Immune checkpoint blockade - Abstract
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 (mTOR) kinase and suppresses the activation of mTORC1, 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., Graphical abstract This study reveals a previously unrecognized antitumor mechanism of tubeimoside-1 and represents an alternative immune checkpoint blockade therapeutic strategy to enhance the efficacy of cancer immunotherapy.Image 1
- Published
- 2021