Joanna Kopecka1, Iris C Salaroglio2, Luisella Righi3, Roberta Libener4, Sara Orecchia5, Federica Grosso6, Vladan Milosevic7, Preeta Ananthanarayanan8, Luisa Ricci9, Enrica Capelletto10, Monica Pradotto11, Francesca Napoli12, Massimo Di Maio13, Silvia Novello14, Menachem Rubinstein15, Giorgio V Scagliotti16, Chiara Riganti17. 1. Department of Oncology, University of Torino, via Santena 5/bis, 10126, Torino, Italy. Electronic address: joanna.kopecka@unito.it. 2. Department of Oncology, University of Torino, via Santena 5/bis, 10126, Torino, Italy. Electronic address: irischiara.salaroglio@unito.it. 3. Pathology Unit, Department of Oncology at San Luigi Hospital, University of Torino, Regione Gonzole 10, 10043, Orbassano, Italy. Electronic address: luisella.righi@unito.it. 4. Pathology Division, S. Antonio and Biagio Hospital, Spalto Marengo, 15121, Alessandria, Italy. Electronic address: rlibener@ospedale.al.it. 5. Pathology Division, S. Antonio and Biagio Hospital, Spalto Marengo, 15121, Alessandria, Italy. Electronic address: sorecchia@ospedale.al.it. 6. Oncology Division, S. Antonio and Biagio Hospital, Spalto Marengo, 15121, Alessandria, Italy. Electronic address: fgrosso@ospedale.al.it. 7. Department of Oncology, University of Torino, via Santena 5/bis, 10126, Torino, Italy. Electronic address: vladan.milosevic@unito.it. 8. Department of Oncology, University of Torino, via Santena 5/bis, 10126, Torino, Italy. Electronic address: preeta.ananthanarayanan@unito.it. 9. Department of Oncology, University of Torino, via Santena 5/bis, 10126, Torino, Italy. Electronic address: luisa.ricci@gmail.com. 10. Thoracic Unit and Medical Oncology Division, Department of Oncology at San Luigi Hospital, Regione Gonzole 10, University of Torino, Orbassano, Italy. Electronic address: enrica.capelletto@gmail.com. 11. Thoracic Unit and Medical Oncology Division, Department of Oncology at San Luigi Hospital, Regione Gonzole 10, University of Torino, Orbassano, Italy. Electronic address: monica.pradotto@unito.it. 12. Pathology Unit, Department of Oncology at San Luigi Hospital, University of Torino, Regione Gonzole 10, 10043, Orbassano, Italy. Electronic address: francesca.napoli@unito.it. 13. Medical Oncology Division, Department of Oncology at Mauriziano Hospital, Largo Filippo Turati 62, 10128, University of Torino, Italy. Electronic address: massimo.dimaio@unito.it. 14. Thoracic Unit and Medical Oncology Division, Department of Oncology at San Luigi Hospital, Regione Gonzole 10, University of Torino, Orbassano, Italy. Electronic address: silvia.novello@unito.it. 15. Department of Molecular Genetics, The Weizmann Institute of Science, Herzl Street 234, 76100, Rehovot, Israel. Electronic address: menachem.rubinstein@weizmann.ac.il. 16. Thoracic Unit and Medical Oncology Division, Department of Oncology at San Luigi Hospital, Regione Gonzole 10, University of Torino, Orbassano, Italy. Electronic address: giorgio.scagliotti@unito.it. 17. Department of Oncology, University of Torino, via Santena 5/bis, 10126, Torino, Italy. Electronic address: chiara.riganti@unito.it.
Abstract
OBJECTIVES: Cisplatin-based chemotherapy is moderately active in malignant pleural mesothelioma (MPM) due to intrinsic drug resistance and to low immunogenicity of MPM cells. CAAT/enhancer binding protein (C/EBP)-β LIP is a pro-apoptotic and chemosensitizing transcription factor activated in response to endoplasmic reticulum (ER) stress. MATERIALS AND METHODS: We investigated if LIP levels can predict the clinical response to cisplatin and survival of MPM patients receiving cisplatin-based chemotherapy. We studied the LIP-dependent mechanisms determining cisplatin-resistance and we identified pharmacological approaches targeting LIP, able to restore cisplatin sensitiveness, in patient-derived MPM cells and animal models. Results were analyzed by a one-way analysis of variance test. RESULTS: We found that LIP was degraded by constitutive ubiquitination in primary MPM cells derived from patients poorly responsive to cisplatin. LIP ubiquitination was directly correlated with cisplatin chemosensitivity and was associated with patients' survival after chemotherapy. Overexpression of LIP restored cisplatin's pro-apoptotic effect by activating CHOP/TRB3/caspase 3 axis and up-regulating calreticulin, that triggered MPM cell phagocytosis by dendritic cells and expanded autologous anti-tumor CD8+CD107+T-cytotoxic lymphocytes. Proteasome inhibitor carfilzomib and lysosome inhibitor chloroquine prevented LIP degradation. The triple combination of carfilzomib, chloroquine and cisplatin increased ER stress-triggered apoptosis and immunogenic cell death in patients' samples, and reduced tumor growth in cisplatin-resistant MPM preclinical models. CONCLUSION: The loss of LIP mediates cisplatin resistance, rendering LIP a possible predictor of cisplatin response in MPM patients. The association of proteasome and lysosome inhibitors reverses cisplatin resistance by restoring LIP levels and may represent a new adjuvant strategy in MPM treatment.
OBJECTIVES:Cisplatin-based chemotherapy is moderately active in malignant pleural mesothelioma (MPM) due to intrinsic drug resistance and to low immunogenicity of MPM cells. CAAT/enhancer binding protein (C/EBP)-β LIP is a pro-apoptotic and chemosensitizing transcription factor activated in response to endoplasmic reticulum (ER) stress. MATERIALS AND METHODS: We investigated if LIP levels can predict the clinical response to cisplatin and survival of MPM patients receiving cisplatin-based chemotherapy. We studied the LIP-dependent mechanisms determining cisplatin-resistance and we identified pharmacological approaches targeting LIP, able to restore cisplatin sensitiveness, in patient-derived MPM cells and animal models. Results were analyzed by a one-way analysis of variance test. RESULTS: We found that LIP was degraded by constitutive ubiquitination in primary MPM cells derived from patients poorly responsive to cisplatin. LIP ubiquitination was directly correlated with cisplatin chemosensitivity and was associated with patients' survival after chemotherapy. Overexpression of LIP restored cisplatin's pro-apoptotic effect by activating CHOP/TRB3/caspase 3 axis and up-regulating calreticulin, that triggered MPM cell phagocytosis by dendritic cells and expanded autologous anti-tumor CD8+CD107+T-cytotoxic lymphocytes. Proteasome inhibitor carfilzomib and lysosome inhibitor chloroquine prevented LIP degradation. The triple combination of carfilzomib, chloroquine and cisplatin increased ER stress-triggered apoptosis and immunogenic cell death in patients' samples, and reduced tumor growth in cisplatin-resistant MPM preclinical models. CONCLUSION: The loss of LIP mediates cisplatin resistance, rendering LIP a possible predictor of cisplatin response in MPM patients. The association of proteasome and lysosome inhibitors reverses cisplatin resistance by restoring LIP levels and may represent a new adjuvant strategy in MPM treatment.
Authors: Lorenzo Galluzzi; Ilio Vitale; Sarah Warren; Sandy Adjemian; Patrizia Agostinis; Aitziber Buqué Martinez; Timothy A Chan; George Coukos; Sandra Demaria; Eric Deutsch; Dobrin Draganov; Richard L Edelson; Silvia C Formenti; Jitka Fucikova; Lucia Gabriele; Udo S Gaipl; Sofia R Gameiro; Abhishek D Garg; Encouse Golden; Jian Han; Kevin J Harrington; Akseli Hemminki; James W Hodge; Dewan Md Sakib Hossain; Tim Illidge; Michael Karin; Howard L Kaufman; Oliver Kepp; Guido Kroemer; Juan Jose Lasarte; Sherene Loi; Michael T Lotze; Gwenola Manic; Taha Merghoub; Alan A Melcher; Karen L Mossman; Felipe Prosper; Øystein Rekdal; Maria Rescigno; Chiara Riganti; Antonella Sistigu; Mark J Smyth; Radek Spisek; John Stagg; Bryan E Strauss; Daolin Tang; Kazuki Tatsuno; Stefaan W van Gool; Peter Vandenabeele; Takahiro Yamazaki; Dmitriy Zamarin; Laurence Zitvogel; Alessandra Cesano; Francesco M Marincola Journal: J Immunother Cancer Date: 2020-03 Impact factor: 13.751
Authors: Marie Shamseddin; Joanna Obacz; Mathew J Garnett; Robert Campbell Rintoul; Hayley Elizabeth Francies; Stefan John Marciniak Journal: Thorax Date: 2021-03-10 Impact factor: 9.139