ZEB1 transcription factor promotes immune escape in melanoma

作者：Maud Plaschka, Valentin Benboubker, Maxime Grimont, Justine Berthet, Laurie Tonon, Jonathan Lopez, Myrtille Le-Bouar, B. Balme, G Tondeur, Arnaud de la Fouchardière, Lionel Larue, Alain Puisieux, Yenkel Grinberg‐Bleyer, Nathalie Bendriss‐Vermare, Bertrand Dubois, Christophe Caux, Stéphane Dalle, Julie Caramel · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2022 · DOI：10.1136/jitc-2021-003484 · 被引用次数：107 · 研究领域：Cancer Immunotherapy and Biomarkers、Melanoma and MAPK Pathways、Immunotherapy and Immune Responses

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 + , CD4 + T cells number and their activation state (PD-1, Ki67). ZEB1 gain-of-function or loss-of-function approaches were then implemented in syngeneic melanoma mouse models, followed by monitoring of tumor growth, quantification of immune cell populations frequency and function by flow cytometry, cytokines secretion by multiplex analyses. Chromatin-immunoprecipitation was us...