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

Author

Listed:
  • Francesca Reggiani

    (Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia)

  • Giovanna Talarico

    (European Institute of Oncology IRCCS
    European Institute of Oncology IRCCS and Politecnico di Milano)

  • Giulia Gobbi

    (Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia)

  • Elisabetta Sauta

    (Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia
    Rozzano)

  • Federica Torricelli

    (Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia)

  • Veronica Manicardi

    (Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia
    University of Modena and Reggio Emilia)

  • Eleonora Zanetti

    (Azienda USL-IRCCS di Reggio Emilia
    Azienda USL-IRCCS di Reggio Emilia)

  • Stefania Orecchioni

    (European Institute of Oncology IRCCS
    European Institute of Oncology IRCCS and Politecnico di Milano)

  • Paolo Falvo

    (European Institute of Oncology IRCCS
    European Institute of Oncology IRCCS and Politecnico di Milano)

  • Simonetta Piana

    (Azienda USL-IRCCS di Reggio Emilia
    Azienda USL-IRCCS di Reggio Emilia)

  • Filippo Lococo

    (Università Cattolica del Sacro Cuore
    Fondazione Policlinico Universitario A. Gemelli IRCCS)

  • Massimiliano Paci

    (Azienda USL-IRCCS di Reggio Emilia)

  • Francesco Bertolini

    (European Institute of Oncology IRCCS
    European Institute of Oncology IRCCS and Politecnico di Milano)

  • Alessia Ciarrocchi

    (Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia)

  • Valentina Sancisi

    (Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia)

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.

Suggested Citation

  • Francesca Reggiani & Giovanna Talarico & Giulia Gobbi & Elisabetta Sauta & Federica Torricelli & Veronica Manicardi & Eleonora Zanetti & Stefania Orecchioni & Paolo Falvo & Simonetta Piana & Filippo L, 2024. "BET inhibitors drive Natural Killer activation in non-small cell lung cancer via BRD4 and SMAD3," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46778-8
    DOI: 10.1038/s41467-024-46778-8
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    References listed on IDEAS

    as
    1. Patrick Ming-Kuen Tang & Shuang Zhou & Xiao-Ming Meng & Qing-Ming Wang & Chun-Jie Li & Guang-Yu Lian & Xiao-Ru Huang & Yong-Jiang Tang & Xin-Yuan Guan & Bryan Ping-Yen Yan & Ka-Fai To & Hui-Yao Lan, 2017. "Smad3 promotes cancer progression by inhibiting E4BP4-mediated NK cell development," Nature Communications, Nature, vol. 8(1), pages 1-15, April.
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