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.

BET inhibitors drive Natural Killer activation in non-small cell lung cancer via BRD4 and SMAD3 / 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. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 15:1(2024), pp. N/A-N/A. [10.1038/s41467-024-46778-8]

BET inhibitors drive Natural Killer activation in non-small cell lung cancer via BRD4 and SMAD3

Manicardi, Veronica;Sancisi, Valentina
2024

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.
2024
15
1
N/A
N/A
BET inhibitors drive Natural Killer activation in non-small cell lung cancer via BRD4 and SMAD3 / 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. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 15:1(2024), pp. N/A-N/A. [10.1038/s41467-024-46778-8]
Reggiani, Francesca; Talarico, Giovanna; Gobbi, Giulia; Sauta, Elisabetta; Torricelli, Federica; Manicardi, Veronica; Zanetti, Eleonora; Orecchioni, S...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1373329
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