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

Francesca Reggiani (), Giovanna Talarico, Giulia Gobbi, Elisabetta Sauta, Federica Torricelli, Veronica Manicardi, Eleonora Zanetti, Stefania Orecchioni, Paolo Falvo, Simonetta Piana, Filippo Lococo, Massimiliano Paci, Francesco Bertolini, Alessia Ciarrocchi and Valentina Sancisi ()
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Francesca Reggiani: Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia
Giovanna Talarico: European Institute of Oncology IRCCS
Giulia Gobbi: Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia
Elisabetta Sauta: Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia
Federica Torricelli: Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia
Veronica Manicardi: Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia
Eleonora Zanetti: Azienda USL-IRCCS di Reggio Emilia
Stefania Orecchioni: European Institute of Oncology IRCCS
Paolo Falvo: European Institute of Oncology IRCCS
Simonetta Piana: Azienda USL-IRCCS di Reggio Emilia
Filippo Lococo: Università Cattolica del Sacro Cuore
Massimiliano Paci: Azienda USL-IRCCS di Reggio Emilia
Francesco Bertolini: European Institute of Oncology IRCCS
Alessia Ciarrocchi: Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia
Valentina Sancisi: Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46778-8

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