Cell Reports (Feb 2024)
ZEB1 shapes AML immunological niches, suppressing CD8 T cell activity while fostering Th17 cell expansion
- Barbara Bassani,
- Giorgia Simonetti,
- Valeria Cancila,
- Antonio Fiorino,
- Marilena Ciciarello,
- Annamaria Piva,
- Arman Mandegar Khorasani,
- Claudia Chiodoni,
- Daniele Lecis,
- Alessandro Gulino,
- Eugenio Fonzi,
- Laura Botti,
- Paola Portararo,
- Massimo Costanza,
- Marta Brambilla,
- Giorgia Colombo,
- Juerg Schwaller,
- Alexandar Tzankov,
- Maurilio Ponzoni,
- Fabio Ciceri,
- Niccolò Bolli,
- Antonio Curti,
- Claudio Tripodo,
- Mario P. Colombo,
- Sabina Sangaletti
Affiliations
- Barbara Bassani
- Molecular Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
- Giorgia Simonetti
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
- Valeria Cancila
- Tumor Immunology Unit, Department of Health Sciences, Human Pathology Section, School of Medicine, University of Palermo, 90133 Palermo, Italy
- Antonio Fiorino
- Predictive Medicine: Molecular Bases of Genetic Risk Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
- Marilena Ciciarello
- CNR Institute of Molecular Genetics “Luigi Luca Cavalli-Sforza,” Unit of Bologna, Bologna, Italy; IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy; Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- Annamaria Piva
- Molecular Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
- Arman Mandegar Khorasani
- Molecular Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
- Claudia Chiodoni
- Molecular Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
- Daniele Lecis
- Molecular Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
- Alessandro Gulino
- CGT Lab, Cogentech Società Benefit, Catania, Italy
- Eugenio Fonzi
- Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori,” Meldola, Forlì-Cesena, Italy
- Laura Botti
- Molecular Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
- Paola Portararo
- Molecular Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
- Massimo Costanza
- Neuro-Oncology Unit, Department of Clinical Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
- Marta Brambilla
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Giorgia Colombo
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy
- Juerg Schwaller
- University Children’s Hospital Basel & Department of Biomedicine, University of Basel, Basel, Switzerland
- Alexandar Tzankov
- Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
- Maurilio Ponzoni
- IRCCS Ospedale S. Raffaele, University Vita-Salute San Raffaele, Milan, Italy
- Fabio Ciceri
- IRCCS Ospedale S. Raffaele, University Vita-Salute San Raffaele, Milan, Italy
- Niccolò Bolli
- Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
- Antonio Curti
- Department of Experimental, Diagnostic and Specialty Medicine – DIMES, Institute of Hematology “Seràgnoli,” Bologna, Italy
- Claudio Tripodo
- Tumor Immunology Unit, Department of Health Sciences, Human Pathology Section, School of Medicine, University of Palermo, 90133 Palermo, Italy; IFOM-ETS-The AIRC Institute of Molecular Oncology, Milan, Italy
- Mario P. Colombo
- Molecular Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; Corresponding author
- Sabina Sangaletti
- Molecular Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; Corresponding author
- Journal volume & issue
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Vol. 43,
no. 2
p. 113794
Abstract
Summary: Acute myeloid leukemia (AML) progression is influenced by immune suppression induced by leukemia cells. ZEB1, a critical transcription factor in epithelial-to-mesenchymal transition, demonstrates immune regulatory functions in AML. Silencing ZEB1 in leukemic cells reduces engraftment and extramedullary disease in immune-competent mice, activating CD8 T lymphocytes and limiting Th17 cell expansion. ZEB1 in AML cells directly promotes Th17 cell development that, in turn, creates a self-sustaining loop and a pro-invasive phenotype, favoring transforming growth factor β (TGF-β), interleukin-23 (IL-23), and SOCS2 gene transcription. In bone marrow biopsies from AML patients, immunohistochemistry shows a direct correlation between ZEB1 and Th17. Also, the analysis of ZEB1 expression in larger datasets identifies two distinct AML groups, ZEB1high and ZEB1low, each with specific immunological and molecular traits. ZEB1high patients exhibit increased IL-17, SOCS2, and TGF-β pathways and a negative association with overall survival. This unveils ZEB1’s dual role in AML, entwining pro-tumoral and immune regulatory capacities in AML blasts.
