BET inhibitors drive Natural Killer activation in non-small cell lung cancer via BRD4 and SMAD3.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 Mar 2024
22 Mar 2024
Historique:
received:
31
03
2023
accepted:
11
03
2024
medline:
23
3
2024
pubmed:
23
3
2024
entrez:
23
3
2024
Statut:
epublish
Résumé
Non-small-cell lung carcinoma (NSCLC) is the most common lung cancer and one of the pioneer tumors in which immunotherapy has radically changed patients' outcomes. However, several issues are emerging and their implementation is required to optimize immunotherapy-based protocols. In this work, we investigate the ability of the Bromodomain and Extra-Terminal protein inhibitors (BETi) to stimulate a proficient anti-tumor immune response toward NSCLC. By using in vitro, ex-vivo, and in vivo models, we demonstrate that these epigenetic drugs specifically enhance Natural Killer (NK) cell cytotoxicity. BETi down-regulate a large set of NK inhibitory receptors, including several immune checkpoints (ICs), that are direct targets of the transcriptional cooperation between the BET protein BRD4 and the transcription factor SMAD3. Overall, BETi orchestrate an epigenetic reprogramming that leads to increased recognition of tumor cells and the killing ability of NK cells. Our results unveil the opportunity to exploit and repurpose these drugs in combination with immunotherapy.
Identifiants
pubmed: 38519469
doi: 10.1038/s41467-024-46778-8
pii: 10.1038/s41467-024-46778-8
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2567Subventions
Organisme : Ministero della Salute (Ministry of Health, Italy)
ID : Bando per la Valorizzazione della Ricerca Istituzionale 2021 - Fondi 5 per Mille 2016
Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
ID : IG26377
Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
ID : IG20109
Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
ID : IG21772
Organisme : Fondazione Umberto Veronesi (Umberto Veronesi Foundation)
ID : Fellowship
Informations de copyright
© 2024. The Author(s).
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