Bromodomain inhibition exerts its therapeutic potential in malignant pleural mesothelioma by promoting immunogenic cell death and changing the tumor immune-environment

Chiara Riganti, Marcello Francesco Lingua, Iris Chiara Salaroglio, Chiara Falcomatà, Luisella Righi, Deborah Morena, Francesca Picca, Daniele Oddo, Joanna Kopecka, Monica Pradotto, Roberta Libener, Sara Orecchia, Paolo Bironzo, Valentina Comunanza, Federico Bussolino, Silvia Novello, Giorgio Vittorio Scagliotti, Federica Di Nicolantonio, Riccardo Taulli

Research output: Contribution to journalArticle

Abstract

Systemic treatment of malignant pleural mesothelioma (MPM) is moderately active for the intrinsic pharmacological resistance of MPM cell and its ability to induce an immune suppressive environment. Here we showed that the expression of bromodomain (BRD) proteins BRD2, BRD4 and BRD9 was significantly higher in human primary MPM cells compared to normal mesothelial cells (HMC). Nanomolar concentrations of bromodomain inhibitors (BBIs) JQ1 or OTX015 impaired patient-derived MPM cell proliferation and induced cell-cycle arrest without affecting apoptosis. Importantly, BBIs primed MPM cells for immunogenic cell death, by increasing extracellular release of ATP and HMGB1, and by promoting membrane exposure of calreticulin and ERp57. Accordingly, BBIs activated dendritic cell (DC)-mediated phagocytosis and expansion of CD8+ T-lymphocyte clones endorsed with antitumor cytotoxic activity. BBIs reduced the expression of the immune checkpoint ligand PD-L1 in MPM cells; while both CD8+ and CD4+ T-lymphocytes co-cultured with JQ1-treated MPM cells decreased PD-1 expression, suggesting a disruption of the immune-suppressive PD-L1/PD-1 axis. Additionally, BBIs reduced the expansion of myeloid-derived suppressor cells (MDSC) induced by MPM cells. Finally, a preclinical model of MPM confirmed that the anti-tumor efficacy of JQ1 was largely due to its ability to restore an immune-active environment, by increasing intra-tumor DC and CD8+ T-lymphocytes, and decreasing MDSC. Thereby, we propose that, among novel drugs, BBIs should be investigated for MPM treatment for their combined activity on both tumor cells and surrounding immune-environment.

Original languageEnglish
Pages (from-to)e1398874
JournalOncoImmunology
Volume7
Issue number3
DOIs
Publication statusPublished - 2018

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Cell Death
Neoplasms
Therapeutics
T-Lymphocytes
Dendritic Cells
Malignant Mesothelioma
Calreticulin
HMGB1 Protein
Cytophagocytosis
Cell Cycle Checkpoints
Clone Cells
Adenosine Triphosphate
Cell Proliferation
Pharmacology
Apoptosis
Ligands
Membranes
Pharmaceutical Preparations
Proteins

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Bromodomain inhibition exerts its therapeutic potential in malignant pleural mesothelioma by promoting immunogenic cell death and changing the tumor immune-environment. / Riganti, Chiara; Lingua, Marcello Francesco; Salaroglio, Iris Chiara; Falcomatà, Chiara; Righi, Luisella; Morena, Deborah; Picca, Francesca; Oddo, Daniele; Kopecka, Joanna; Pradotto, Monica; Libener, Roberta; Orecchia, Sara; Bironzo, Paolo; Comunanza, Valentina; Bussolino, Federico; Novello, Silvia; Scagliotti, Giorgio Vittorio; Di Nicolantonio, Federica; Taulli, Riccardo.

In: OncoImmunology, Vol. 7, No. 3, 2018, p. e1398874.

Research output: Contribution to journalArticle

Riganti, C, Lingua, MF, Salaroglio, IC, Falcomatà, C, Righi, L, Morena, D, Picca, F, Oddo, D, Kopecka, J, Pradotto, M, Libener, R, Orecchia, S, Bironzo, P, Comunanza, V, Bussolino, F, Novello, S, Scagliotti, GV, Di Nicolantonio, F & Taulli, R 2018, 'Bromodomain inhibition exerts its therapeutic potential in malignant pleural mesothelioma by promoting immunogenic cell death and changing the tumor immune-environment', OncoImmunology, vol. 7, no. 3, pp. e1398874. https://doi.org/10.1080/2162402X.2017.1398874
Riganti, Chiara ; Lingua, Marcello Francesco ; Salaroglio, Iris Chiara ; Falcomatà, Chiara ; Righi, Luisella ; Morena, Deborah ; Picca, Francesca ; Oddo, Daniele ; Kopecka, Joanna ; Pradotto, Monica ; Libener, Roberta ; Orecchia, Sara ; Bironzo, Paolo ; Comunanza, Valentina ; Bussolino, Federico ; Novello, Silvia ; Scagliotti, Giorgio Vittorio ; Di Nicolantonio, Federica ; Taulli, Riccardo. / Bromodomain inhibition exerts its therapeutic potential in malignant pleural mesothelioma by promoting immunogenic cell death and changing the tumor immune-environment. In: OncoImmunology. 2018 ; Vol. 7, No. 3. pp. e1398874.
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T1 - Bromodomain inhibition exerts its therapeutic potential in malignant pleural mesothelioma by promoting immunogenic cell death and changing the tumor immune-environment

AU - Riganti, Chiara

AU - Lingua, Marcello Francesco

AU - Salaroglio, Iris Chiara

AU - Falcomatà, Chiara

AU - Righi, Luisella

AU - Morena, Deborah

AU - Picca, Francesca

AU - Oddo, Daniele

AU - Kopecka, Joanna

AU - Pradotto, Monica

AU - Libener, Roberta

AU - Orecchia, Sara

AU - Bironzo, Paolo

AU - Comunanza, Valentina

AU - Bussolino, Federico

AU - Novello, Silvia

AU - Scagliotti, Giorgio Vittorio

AU - Di Nicolantonio, Federica

AU - Taulli, Riccardo

PY - 2018

Y1 - 2018

N2 - Systemic treatment of malignant pleural mesothelioma (MPM) is moderately active for the intrinsic pharmacological resistance of MPM cell and its ability to induce an immune suppressive environment. Here we showed that the expression of bromodomain (BRD) proteins BRD2, BRD4 and BRD9 was significantly higher in human primary MPM cells compared to normal mesothelial cells (HMC). Nanomolar concentrations of bromodomain inhibitors (BBIs) JQ1 or OTX015 impaired patient-derived MPM cell proliferation and induced cell-cycle arrest without affecting apoptosis. Importantly, BBIs primed MPM cells for immunogenic cell death, by increasing extracellular release of ATP and HMGB1, and by promoting membrane exposure of calreticulin and ERp57. Accordingly, BBIs activated dendritic cell (DC)-mediated phagocytosis and expansion of CD8+ T-lymphocyte clones endorsed with antitumor cytotoxic activity. BBIs reduced the expression of the immune checkpoint ligand PD-L1 in MPM cells; while both CD8+ and CD4+ T-lymphocytes co-cultured with JQ1-treated MPM cells decreased PD-1 expression, suggesting a disruption of the immune-suppressive PD-L1/PD-1 axis. Additionally, BBIs reduced the expansion of myeloid-derived suppressor cells (MDSC) induced by MPM cells. Finally, a preclinical model of MPM confirmed that the anti-tumor efficacy of JQ1 was largely due to its ability to restore an immune-active environment, by increasing intra-tumor DC and CD8+ T-lymphocytes, and decreasing MDSC. Thereby, we propose that, among novel drugs, BBIs should be investigated for MPM treatment for their combined activity on both tumor cells and surrounding immune-environment.

AB - Systemic treatment of malignant pleural mesothelioma (MPM) is moderately active for the intrinsic pharmacological resistance of MPM cell and its ability to induce an immune suppressive environment. Here we showed that the expression of bromodomain (BRD) proteins BRD2, BRD4 and BRD9 was significantly higher in human primary MPM cells compared to normal mesothelial cells (HMC). Nanomolar concentrations of bromodomain inhibitors (BBIs) JQ1 or OTX015 impaired patient-derived MPM cell proliferation and induced cell-cycle arrest without affecting apoptosis. Importantly, BBIs primed MPM cells for immunogenic cell death, by increasing extracellular release of ATP and HMGB1, and by promoting membrane exposure of calreticulin and ERp57. Accordingly, BBIs activated dendritic cell (DC)-mediated phagocytosis and expansion of CD8+ T-lymphocyte clones endorsed with antitumor cytotoxic activity. BBIs reduced the expression of the immune checkpoint ligand PD-L1 in MPM cells; while both CD8+ and CD4+ T-lymphocytes co-cultured with JQ1-treated MPM cells decreased PD-1 expression, suggesting a disruption of the immune-suppressive PD-L1/PD-1 axis. Additionally, BBIs reduced the expansion of myeloid-derived suppressor cells (MDSC) induced by MPM cells. Finally, a preclinical model of MPM confirmed that the anti-tumor efficacy of JQ1 was largely due to its ability to restore an immune-active environment, by increasing intra-tumor DC and CD8+ T-lymphocytes, and decreasing MDSC. Thereby, we propose that, among novel drugs, BBIs should be investigated for MPM treatment for their combined activity on both tumor cells and surrounding immune-environment.

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