ZEB1 transcription factor induces tumor cell PD-L1 expression in melanoma

ZEB1 transcription factor induces tumor cell PD-L1 expression in melanoma

Abstract Tumor cells can evade antitumor immune response by expressing the PD-L1 ligand, leading to the inhibition of PD-1-expressing T lymphocytes. The mechanisms that regulate PD-L1 expression in cancer cells are imperfectly characterized. The transcription factor ZEB1, a major regulator of phenot...

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Main Authors: Chloé Wirbel, Simon Durand, Félix Boivin, Maud Plaschka, Valentin Benboubker, Maxime Grimont, Laetitia Barbollat-Boutrand, Garance Tondeur, Brigitte Balme, Olivier Harou, Anaïs Eberhardt, Stéphane Dalle, Jonathan Lopez, Julie Caramel
Format: Article
Language:English
Published: Springer 2025-03-01
Series:Cancer Immunology, Immunotherapy
Subjects:
Melanoma
ZEB1
PD-L1
Phenotype switching
Pseudo-EMT
Online Access:https://doi.org/10.1007/s00262-025-03978-5
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Summary:Abstract Tumor cells can evade antitumor immune response by expressing the PD-L1 ligand, leading to the inhibition of PD-1-expressing T lymphocytes. The mechanisms that regulate PD-L1 expression in cancer cells are imperfectly characterized. The transcription factor ZEB1, a major regulator of phenotype switching in melanoma cells, was shown to promote immune escape in melanoma by repressing T cell infiltration. Using inducible models of phenotype switching and ZEB1 gain/loss-of-function melanoma, we show that ZEB1 binds to the CD274 (PD-L1) promoter, directly enhancing PD-L1 mRNA transcription and its expression at the cell membrane. Furthermore, using single-cell spatial analyses on human primary melanoma samples, we demonstrate the correlation of ZEB1 and PD-L1 expression in tumor cells. Overall, these data identify ZEB1-mediated regulation of PD-L1 tumor expression as a mechanism that could contribute to immune escape in melanoma.
ISSN:1432-0851

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