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
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（10）
• 所属期刊栏目: Original articles
• 页码范围: 3134-3149
• 页数: 16页
• 语种: 英文

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-L 1 level.TBM-1 disrupts PD-1/PD-L1 interaction and enhances the cytotox-icity 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 B 16 melanoma tumor xenograft via activating tumor-infiltrating T-cell immunity.Mechanistically,TBM-1 triggers PD-L1 lyso-somal 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 previ-ously unrecognized antitumor mechanism of TBM-1 and represent an alternative ICB therapeutic strategy to enhance the efficacy of cancer immunotherapy.