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

  • Nat Commun. 2024 Mar 22;15(1):2567. doi: 10.1038/s41467-024-46778-8.
Francesca Reggiani  1 ,  Giovanna Talarico  2  3 ,  Giulia Gobbi  4 ,  Elisabetta Sauta  4  5 ,  Federica Torricelli  4 ,  Veronica Manicardi  4  6 ,  Eleonora Zanetti  7  8 ,  Stefania Orecchioni  2  3 ,  Paolo Falvo  2  3 ,  Simonetta Piana  7  8 ,  Filippo Lococo  9  10 ,  Massimiliano Paci  11 ,  Francesco Bertolini  2  3 ,  Alessia Ciarrocchi  4 ,  Valentina Sancisi  12
Affiliations
  • 1. Translational Research Laboratory, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy. [email protected].
  • 2. Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Milan, Italy.
  • 3. Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy.
  • 4. Translational Research Laboratory, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
  • 5. Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy.
  • 6. Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy.
  • 7. Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
  • 8. Biobank, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
  • 9. Università Cattolica del Sacro Cuore, Rome, Italy.
  • 10. Department of General Thoracic Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
  • 11. Thoracic Surgery Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
  • 12. Translational Research Laboratory, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy. [email protected].
PMID: 38519469 DOI: 10.1038/s41467-024-46778-8
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.

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