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IL-33 Promotes CD11b/CD18-Mediated Adhesion of Eosinophils to Cancer Cells and Synapse-Polarized Degranulation Leading to Tumor Cell Killing

Eosinophils are major effectors of Th2-related pathologies, frequently found infiltrating several human cancers. We recently showed that eosinophils play an essential role in anti-tumor responses mediated by immunotherapy with the ‘alarmin’ intereukin-33 (IL-33) in melanoma mouse models. Here, we an...

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Autores principales: Andreone, Sara, Spadaro, Francesca, Buccione, Carla, Mancini, Jacopo, Tinari, Antonella, Sestili, Paola, Gambardella, Adriana Rosa, Lucarini, Valeria, Ziccheddu, Giovanna, Parolini, Isabella, Zanetti, Cristiana, D’Urso, Maria Teresa, De Ninno, Adele, Businaro, Luca, Afferni, Claudia, Mattei, Fabrizio, Schiavoni, Giovanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895824/
https://www.ncbi.nlm.nih.gov/pubmed/31717819
http://dx.doi.org/10.3390/cancers11111664
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author Andreone, Sara
Spadaro, Francesca
Buccione, Carla
Mancini, Jacopo
Tinari, Antonella
Sestili, Paola
Gambardella, Adriana Rosa
Lucarini, Valeria
Ziccheddu, Giovanna
Parolini, Isabella
Zanetti, Cristiana
D’Urso, Maria Teresa
De Ninno, Adele
Businaro, Luca
Afferni, Claudia
Mattei, Fabrizio
Schiavoni, Giovanna
author_facet Andreone, Sara
Spadaro, Francesca
Buccione, Carla
Mancini, Jacopo
Tinari, Antonella
Sestili, Paola
Gambardella, Adriana Rosa
Lucarini, Valeria
Ziccheddu, Giovanna
Parolini, Isabella
Zanetti, Cristiana
D’Urso, Maria Teresa
De Ninno, Adele
Businaro, Luca
Afferni, Claudia
Mattei, Fabrizio
Schiavoni, Giovanna
author_sort Andreone, Sara
collection PubMed
description Eosinophils are major effectors of Th2-related pathologies, frequently found infiltrating several human cancers. We recently showed that eosinophils play an essential role in anti-tumor responses mediated by immunotherapy with the ‘alarmin’ intereukin-33 (IL-33) in melanoma mouse models. Here, we analyzed the mechanisms by which IL-33 mediates tumor infiltration and antitumor activities of eosinophils. We show that IL-33 recruits eosinophils indirectly, via stimulation of tumor cell-derived chemokines, while it activates eosinophils directly, up-regulating CD69, the adhesion molecules ICAM-1 and CD11b/CD18, and the degranulation marker CD63. In co-culture experiments with four different tumor cell lines, IL-33-activated eosinophils established large numbers of stable cell conjugates with target tumor cells, with the polarization of eosinophil effector proteins (ECP, EPX, and granzyme-B) and CD11b/CD18 to immune synapses, resulting in efficient contact-dependent degranulation and tumor cell killing. In tumor-bearing mice, IL-33 induced substantial accumulation of degranulating eosinophils within tumor necrotic areas, indicating cytotoxic activity in vivo. Blocking of CD11b/CD18 signaling significantly reduced IL-33-activated eosinophils’ binding and subsequent killing of tumor cells, indicating a crucial role for this integrin in triggering degranulation. Our findings provide novel mechanistic insights for eosinophil-mediated anti-tumoral function driven by IL-33. Treatments enabling tumor infiltration and proper activation of eosinophils may improve therapeutic response in cancer patients.
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spelling pubmed-68958242019-12-24 IL-33 Promotes CD11b/CD18-Mediated Adhesion of Eosinophils to Cancer Cells and Synapse-Polarized Degranulation Leading to Tumor Cell Killing Andreone, Sara Spadaro, Francesca Buccione, Carla Mancini, Jacopo Tinari, Antonella Sestili, Paola Gambardella, Adriana Rosa Lucarini, Valeria Ziccheddu, Giovanna Parolini, Isabella Zanetti, Cristiana D’Urso, Maria Teresa De Ninno, Adele Businaro, Luca Afferni, Claudia Mattei, Fabrizio Schiavoni, Giovanna Cancers (Basel) Article Eosinophils are major effectors of Th2-related pathologies, frequently found infiltrating several human cancers. We recently showed that eosinophils play an essential role in anti-tumor responses mediated by immunotherapy with the ‘alarmin’ intereukin-33 (IL-33) in melanoma mouse models. Here, we analyzed the mechanisms by which IL-33 mediates tumor infiltration and antitumor activities of eosinophils. We show that IL-33 recruits eosinophils indirectly, via stimulation of tumor cell-derived chemokines, while it activates eosinophils directly, up-regulating CD69, the adhesion molecules ICAM-1 and CD11b/CD18, and the degranulation marker CD63. In co-culture experiments with four different tumor cell lines, IL-33-activated eosinophils established large numbers of stable cell conjugates with target tumor cells, with the polarization of eosinophil effector proteins (ECP, EPX, and granzyme-B) and CD11b/CD18 to immune synapses, resulting in efficient contact-dependent degranulation and tumor cell killing. In tumor-bearing mice, IL-33 induced substantial accumulation of degranulating eosinophils within tumor necrotic areas, indicating cytotoxic activity in vivo. Blocking of CD11b/CD18 signaling significantly reduced IL-33-activated eosinophils’ binding and subsequent killing of tumor cells, indicating a crucial role for this integrin in triggering degranulation. Our findings provide novel mechanistic insights for eosinophil-mediated anti-tumoral function driven by IL-33. Treatments enabling tumor infiltration and proper activation of eosinophils may improve therapeutic response in cancer patients. MDPI 2019-10-26 /pmc/articles/PMC6895824/ /pubmed/31717819 http://dx.doi.org/10.3390/cancers11111664 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Andreone, Sara
Spadaro, Francesca
Buccione, Carla
Mancini, Jacopo
Tinari, Antonella
Sestili, Paola
Gambardella, Adriana Rosa
Lucarini, Valeria
Ziccheddu, Giovanna
Parolini, Isabella
Zanetti, Cristiana
D’Urso, Maria Teresa
De Ninno, Adele
Businaro, Luca
Afferni, Claudia
Mattei, Fabrizio
Schiavoni, Giovanna
IL-33 Promotes CD11b/CD18-Mediated Adhesion of Eosinophils to Cancer Cells and Synapse-Polarized Degranulation Leading to Tumor Cell Killing
title IL-33 Promotes CD11b/CD18-Mediated Adhesion of Eosinophils to Cancer Cells and Synapse-Polarized Degranulation Leading to Tumor Cell Killing
title_full IL-33 Promotes CD11b/CD18-Mediated Adhesion of Eosinophils to Cancer Cells and Synapse-Polarized Degranulation Leading to Tumor Cell Killing
title_fullStr IL-33 Promotes CD11b/CD18-Mediated Adhesion of Eosinophils to Cancer Cells and Synapse-Polarized Degranulation Leading to Tumor Cell Killing
title_full_unstemmed IL-33 Promotes CD11b/CD18-Mediated Adhesion of Eosinophils to Cancer Cells and Synapse-Polarized Degranulation Leading to Tumor Cell Killing
title_short IL-33 Promotes CD11b/CD18-Mediated Adhesion of Eosinophils to Cancer Cells and Synapse-Polarized Degranulation Leading to Tumor Cell Killing
title_sort il-33 promotes cd11b/cd18-mediated adhesion of eosinophils to cancer cells and synapse-polarized degranulation leading to tumor cell killing
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895824/
https://www.ncbi.nlm.nih.gov/pubmed/31717819
http://dx.doi.org/10.3390/cancers11111664
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