- Home >
- Publications >
- ZEB1 transcription factor promotes immune escape in melanoma
ZEB1 transcription factor promotes immune escape in melanoma
Authors
Maud Plaschka, Valentin Benboubker, Maxime Grimont, Justine Berthet, Laurie Tonon, Jonathan Lopez, Myrtille Le-Bouar, Brigitte Balme, Garance Tondeur, Arnaud de la Fouchardière, Lionel Larue, Alain Puisieux, Yenkel Grinberg-Bleyer, Nathalie Bendriss-Vermare, Bertrand Dubois, Christophe Caux, Stéphane Dalle, Julie Caramel
Abstract
Background
The efficacy of immunotherapies in metastatic melanoma depends on a robust T cell infiltration. Oncogenic alterations of tumor cells have been associated to T cell exclusion. Identifying novel cancer cell-intrinsic non-genetic mechanisms of immune escape, the targeting of which would reinstate T cell recruitment, would allow to restore the response to anti-programmed cell death protein 1 (PD-1) antibody therapy. The epithelial-to-mesenchymal transition (EMT)-inducing transcription factor ZEB1 is a major regulator of melanoma cell plasticity, driving resistance to mitogen-activated protein kinase (MAPK) targeted therapies. We thus wondered whether ZEB1 signaling in melanoma cells may promote immune evasion and resistance to immunotherapy.
Methods
We evaluated the putative correlation between ZEB1 expression in melanoma cells and the composition of the immune infiltrate in a cohort of 60 human melanoma samples by combining transcriptomic (RNA-sequencing) and seven-color spatial multi-immunofluorescence analyses. Algorithm-based spatial reconstitution of tumors allowed the quantification of CD8
Results
Combined spatial and transcriptomic analyses of the immune infiltrates in human melanoma samples demonstrated that ZEB1 expression in melanoma cells is associated with decreased CD8
Conclusions
We identify the ZEB1 transcription factor as a key determinant of melanoma immune escape, highlighting a previously unknown therapeutic target to increase efficacy of immunotherapy in melanoma.
Trial registration number
Members

LIONEL LARUE
Directeur de recherche Inserm