A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma.
Cell
; 187(1): 166-183.e25, 2024 01 04.
Article
en En
| MEDLINE
| ID: mdl-38181739
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Melanoma
Límite:
Humans
Idioma:
En
Revista:
Cell
Año:
2024
Tipo del documento:
Article