A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma PMID: 38181739

ADC Targets in Oncology

2026-04-10

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

1. Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium. Electronic address: [email protected].
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: [email protected].
22. Department of General Medical Oncology, UZ Leuven, Leuven, Belgium. Electronic address: [email protected].
23. Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium. Electronic address: [email protected].

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.