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- Title
BET inhibitors drive Natural Killer activation in non-small cell lung cancer via BRD4 and SMAD3.
- Authors
Reggiani, Francesca; Talarico, Giovanna; Gobbi, Giulia; Sauta, Elisabetta; Torricelli, Federica; Manicardi, Veronica; Zanetti, Eleonora; Orecchioni, Stefania; Falvo, Paolo; Piana, Simonetta; Lococo, Filippo; Paci, Massimiliano; Bertolini, Francesco; Ciarrocchi, Alessia; Sancisi, Valentina
- Abstract
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. Combination of BET inhibitors (BETi) with immunotherapy has been reported to be synergic for the treatment of non-small cell lung carcinoma (NSCLC). Here, the authors show that BETi-induced epigenetic reprogramming downregulates the expression of NK cell inhibitory receptors on NK cells, increasing their activation and cytotoxicity against NSCLC.
- Subjects
NON-small-cell lung carcinoma; SMAD proteins; CELL receptors; KILLER cells; IMMUNE checkpoint proteins
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-46778-8