1. Academic Validation
  2. A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma

A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma

  • Cell. 2024 Jan 4;187(1):166-183.e25. doi: 10.1016/j.cell.2023.11.037.
Joanna Pozniak 1 Dennis Pedri 2 Ewout Landeloos 3 Yannick Van Herck 4 Asier Antoranz 5 Lukas Vanwynsberghe 6 Ada Nowosad 6 Niccolò Roda 6 Samira Makhzami 6 Greet Bervoets 6 Lucas Ferreira Maciel 6 Carlos Ariel Pulido-Vicuña 6 Lotte Pollaris 7 Ruth Seurinck 7 Fang Zhao 8 Karine Flem-Karlsen 9 William Damsky 10 Limin Chen 11 Despoina Karagianni 12 Sonia Cinque 13 Sam Kint 14 Katy Vandereyken 14 Benjamin Rombaut 7 Thierry Voet 14 Frank Vernaillen 15 Wim Annaert 16 Diether Lambrechts 17 Veerle Boecxstaens 18 Yvan Saeys 7 Joost van den Oord 19 Francesca Bosisio 19 Panagiotis Karras 6 A Hunter Shain 11 Marcus Bosenberg 20 Eleonora Leucci 13 Annette Paschen 8 Florian Rambow 21 Oliver Bechter 22 Jean-Christophe Marine 23
Affiliations

Affiliations

  • 1 Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium. Electronic address: joanna.pozniak@kuleuven.be.
  • 2 Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium; Laboratory for Membrane Trafficking, Center for Brain and Disease Research, VIB, Leuven, Belgium.
  • 3 Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium; Department of General Medical Oncology, UZ Leuven, Leuven, Belgium.
  • 4 Department of General Medical Oncology, UZ Leuven, Leuven, Belgium.
  • 5 Laboratory of Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven and UZ Leuven, Leuven, Belgium.
  • 6 Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium.
  • 7 Data Mining and Modeling for Biomedicine Group, VIB Center for Inflammation Research, Ghent, Belgium; Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium.
  • 8 Laboratory of Molecular Tumor Immunology, Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site Essen, Essen, Germany.
  • 9 Department of Dermatology, Yale University, 15 York Street, New Haven, CT 05610, USA.
  • 10 Departments of Dermatology and Pathology, Yale University, 15 York Street, New Haven, CT 05610, USA.
  • 11 Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • 12 Immune Regulation and Tumor Immunotherapy Group, Cancer Immunology Unit, Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK.
  • 13 Laboratory for RNA Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
  • 14 Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven, Belgium; KU Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium.
  • 15 Bioinformatics Core, VIB, Ghent, Belgium.
  • 16 Laboratory for Membrane Trafficking, Center for Brain and Disease Research, VIB, Leuven, Belgium.
  • 17 Laboratory of Translational Genetics, Center for Cancer Biology, VIB, Leuven, Belgium; Center for Human Genetics, KU Leuven, Leuven, Belgium.
  • 18 Department of Surgical Oncology, UZ Leuven, Leuven, Belgium.
  • 19 Laboratory of Translational Cell and Tissue Research, Department of Pathology, UZ Leuven, Leuven, Belgium.
  • 20 Departments of Dermatology, Pathology and Immunobiology, Yale University, New Haven, CT 05610, USA.
  • 21 Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium; Department of Applied Computational Cancer Research, Institute for AI in Medicine (IKIM), University Hospital Essen, Essen, Germany; University Duisburg-Essen, Essen, Germany. Electronic address: florian.rambow@uk-essen.de.
  • 22 Department of General Medical Oncology, UZ Leuven, Leuven, Belgium. Electronic address: oliver.bechter@uzleuven.be.
  • 23 Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium. Electronic address: jeanchristophe.marine@kuleuven.be.
Abstract

To better understand intrinsic resistance to immune checkpoint blockade (ICB), we established a comprehensive view of the cellular architecture of the treatment-naive melanoma ecosystem and studied its evolution under ICB. Using single-cell, spatial multi-omics, we showed that the tumor microenvironment promotes the emergence of a complex melanoma transcriptomic landscape. Melanoma cells harboring a mesenchymal-like (MES) state, a population known to confer resistance to targeted therapy, were significantly enriched in early on-treatment biopsies from non-responders to ICB. TCF4 serves as the hub of this landscape by being a master regulator of the MES signature and a suppressor of the melanocytic and antigen presentation transcriptional programs. Targeting TCF4 genetically or pharmacologically, using a bromodomain inhibitor, increased immunogenicity and sensitivity of MES cells to ICB and targeted therapy. We thereby uncovered a TCF4-dependent regulatory network that orchestrates multiple transcriptional programs and contributes to resistance to both targeted therapy and ICB in melanoma.

Keywords

BET inhibition; EMT; TCF4; antigen presentation; checkpoint immunotherapy; dedifferentiation; intra-tumor heterogeneity; melanoma; single-cell transcriptomics; tumor microenvironment.

Figures
Products