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

Joanna Pozniak, Dennis Pedri, Ewout Landeloos, Yannick Van Herck, Asier Antoranz, Lukas Vanwynsberghe, Ada Nowosad, Niccolo Roda, Samira Makhzami, Greet Bervoets, et al.
(2024) CELL. 187(1). p.166-183
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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
TRANSCRIPTION FACTOR E2-2, CLASS-I, CELL STATES, PD-1 BLOCKADE, IMAGE, EXPRESSION, THERAPY, DIFFERENTIATION, PROGRESSION, ECOSYSTEM

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MLA
Pozniak, Joanna, et al. “A TCF4-Dependent Gene Regulatory Network Confers Resistance to Immunotherapy in Melanoma.” CELL, vol. 187, no. 1, 2024, pp. 166–83, doi:10.1016/j.cell.2023.11.037.
APA
Pozniak, J., Pedri, D., Landeloos, E., Van Herck, Y., Antoranz, A., Vanwynsberghe, L., … Marine, J.-C. (2024). A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma. CELL, 187(1), 166–183. https://doi.org/10.1016/j.cell.2023.11.037
Chicago author-date
Pozniak, Joanna, Dennis Pedri, Ewout Landeloos, Yannick Van Herck, Asier Antoranz, Lukas Vanwynsberghe, Ada Nowosad, et al. 2024. “A TCF4-Dependent Gene Regulatory Network Confers Resistance to Immunotherapy in Melanoma.” CELL 187 (1): 166–83. https://doi.org/10.1016/j.cell.2023.11.037.
Chicago author-date (all authors)
Pozniak, Joanna, Dennis Pedri, Ewout Landeloos, Yannick Van Herck, Asier Antoranz, Lukas Vanwynsberghe, Ada Nowosad, Niccolo Roda, Samira Makhzami, Greet Bervoets, Lucas Ferreira Maciel, Carlos Ariel Pulido-Vicuna, Lotte Pollaris, Ruth Seurinck, Fang Zhao, Karine Flem-Karlsen, William Damsky, Limin Chen, Despoina Karagianni, Sonia Cinque, Sam Kint, Katy Vandereyken, Benjamin Rombaut, Thierry Voet, Frank Vernaillen, Wim Annaert, Diether Lambrechts, Veerle Boecxstaens, Yvan Saeys, Joost van den Oord, Francesca Bosisio, Panagiotis Karras, A. Hunter Shain, Marcus Bosenberg, Eleonora Leucci, Annette Paschen, Florian Rambow, Oliver Bechter, and Jean-Christophe Marine. 2024. “A TCF4-Dependent Gene Regulatory Network Confers Resistance to Immunotherapy in Melanoma.” CELL 187 (1): 166–183. doi:10.1016/j.cell.2023.11.037.
Vancouver
1.
Pozniak J, Pedri D, Landeloos E, Van Herck Y, Antoranz A, Vanwynsberghe L, et al. A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma. CELL. 2024;187(1):166–83.
IEEE
[1]
J. Pozniak et al., “A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma,” CELL, vol. 187, no. 1, pp. 166–183, 2024.
@article{01HTF0WP9KF88Q303Q4EN2M5R2,
  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.}},
  author       = {{Pozniak, Joanna and Pedri, Dennis and Landeloos, Ewout and  Van Herck, Yannick and  Antoranz, Asier and  Vanwynsberghe, Lukas and  Nowosad, Ada and  Roda, Niccolo and  Makhzami, Samira and  Bervoets, Greet and  Maciel, Lucas Ferreira and  Pulido-Vicuna, Carlos Ariel and Pollaris, Lotte and Seurinck, Ruth and  Zhao, Fang and  Flem-Karlsen, Karine and  Damsky, William and  Chen, Limin and  Karagianni, Despoina and  Cinque, Sonia and Kint, Sam and  Vandereyken, Katy and Rombaut, Benjamin and  Voet, Thierry and Vernaillen, Frank and  Annaert, Wim and  Lambrechts, Diether and  Boecxstaens, Veerle and Saeys, Yvan and  van den Oord, Joost and  Bosisio, Francesca and  Karras, Panagiotis and  Shain, A. Hunter and  Bosenberg, Marcus and  Leucci, Eleonora and  Paschen, Annette and  Rambow, Florian and  Bechter, Oliver and  Marine, Jean-Christophe}},
  issn         = {{0092-8674}},
  journal      = {{CELL}},
  keywords     = {{TRANSCRIPTION FACTOR E2-2,CLASS-I,CELL STATES,PD-1 BLOCKADE,IMAGE,EXPRESSION,THERAPY,DIFFERENTIATION,PROGRESSION,ECOSYSTEM}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{166--183}},
  title        = {{A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma}},
  url          = {{http://doi.org/10.1016/j.cell.2023.11.037}},
  volume       = {{187}},
  year         = {{2024}},
}
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