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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...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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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. |
format | Online Article Text |
id | pubmed-6895824 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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