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Programmed death-ligand 1 mediates triple-negative breast cancer metastasis and stemness through ten-eleven
Yue Xu1, Jiatian Wang2, Yi Gao2
1MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China; Institute of Reproduction and Development, Shanghai Key Laboratory of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200032, China.
Abstract:
Although the immune checkpoint role of programmed death ligand 1 (PD-L1) is well-established and exploited in cancer immunotherapy, its intrinsic role within tumor biology and therapeutic development remains less understood, largely due to incomplete mechanistic insights. Here, we demonstrate a previously unrecognized mechanism through which PD-L1 drives epithelial-mesenchymal transition (EMT), enhances stemness, and drives metastasis in triple-negative breast cancer (TNBC) cells. Mechanistically, PD-L1 exerts these effects by silencing the anti-metastatic miR-200 family through miR-106b-TET3 axis. Furthermore, PD-L1 knockout is associated with improved tumor outcomes in orthotopic mouse models. Collectively, our findings identify a non-classical function of PD-L1 and TET3 as a critical epigenetic modifier that suppresses PD-L1-mediated EMT and breast cancer stemness during metastatic progression.
Insights
Programmed death ligand 1 (PD-L1) drives triple-negative breast cancer (TNBC) metastasis by promoting epithelial-mesenchymal transition (EMT) and stemness. Silencing the miR-200 family via the miR-106b-TET3 axis underlies this PD-L1 function.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Programmed death ligand 1 (PD-L1) is a key immune checkpoint in cancer immunotherapy.
- Its intrinsic roles in tumor biology, particularly in triple-negative breast cancer (TNBC) metastasis, are not fully understood due to limited mechanistic insights.
Purpose of the Study:
- To elucidate the non-immune checkpoint mechanisms of PD-L1 in TNBC.
- To investigate the role of PD-L1 in driving epithelial-mesenchymal transition (EMT), cancer stemness, and metastasis.
Main Methods:
- Utilized PD-L1 knockout models in TNBC.
- Investigated the miR-106b-TET3 axis and its regulation of the miR-200 family.
- Assessed tumor outcomes in orthotopic mouse models.
Main Results:
- PD-L1 was found to drive EMT, enhance stemness, and promote metastasis in TNBC cells.
- PD-L1 silences the anti-metastatic miR-200 family through the miR-106b-TET3 axis.
- PD-L1 knockout significantly improved tumor outcomes in preclinical models.
Conclusions:
- Identified a novel, non-classical function of PD-L1 in promoting TNBC metastasis.
- TET3 acts as a critical epigenetic modifier suppressing PD-L1-mediated EMT and stemness.
- Findings reveal new therapeutic targets for TNBC progression.
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