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Myeloid-derived suppressor cell depletion therapy targets IL-17A-expressing mammary carcinomas
Triple-negative breast cancer (TNBC) is an invasive subtype of breast cancer but paradoxically associated with increased tumor-infiltrating leukocytes. The molecular and cellular mechanisms underlying TNBC immunobiology are incompletely understood. Interleukin (IL)-17A is a pro-inflammatory cytokine...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414122/ https://www.ncbi.nlm.nih.gov/pubmed/32770025 http://dx.doi.org/10.1038/s41598-020-70231-7 |
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author | Dawod, Bassel Liu, Jinghua Gebremeskel, Simon Yan, Chi Sappong, Antonia Johnston, Brent Hoskin, David W. Marshall, Jean S. Wang, Jun |
author_facet | Dawod, Bassel Liu, Jinghua Gebremeskel, Simon Yan, Chi Sappong, Antonia Johnston, Brent Hoskin, David W. Marshall, Jean S. Wang, Jun |
author_sort | Dawod, Bassel |
collection | PubMed |
description | Triple-negative breast cancer (TNBC) is an invasive subtype of breast cancer but paradoxically associated with increased tumor-infiltrating leukocytes. The molecular and cellular mechanisms underlying TNBC immunobiology are incompletely understood. Interleukin (IL)-17A is a pro-inflammatory cytokine that has both pro- and anti-tumor effects and found in 40–80% of TNBC samples. We report here that IL-17A mRNA and protein are detectable in some human TNBC cell lines and further upregulated by IL-23 and LPS stimulation. Furthermore, the impact of tumor-derived IL-17A in host immune response and tumor growth was examined using murine TNBC 4T1 mammary carcinoma cells transduced with an adenoviral vector expressing IL-17A (AdIL-17A) or control vector (Addl). Compared to Addl-transduction, AdIL-17A-transduction enhanced 4T1 tumor growth and lung metastasis in vivo, which was associated with a marked expansion of myeloid-derived suppressor cells (MDSCs). However, AdIL-17A-transduction also induced strong organ-specific and time-dependent immune activation indicated by dynamic changes of NK cells, B cells, CD4, and CD8 T cells in peripheral blood, lung, and tumor site, as well as the plasma levels of IFNγ. Such findings highlight that tumor-associated IL-17A induces concurrent immune activation and immune suppression. Administration of anti-Gr1 or anti-G-CSF antibody effectively depleted MDSCs in vivo, markedly reducing the growth of AdIL-17A-transduced 4T1 tumors, and eliminating lung metastasis. Collectively, our study demonstrates that MDSC depletion is an effective and practical approach for treating IL-17A-enriched mammary carcinomas. |
format | Online Article Text |
id | pubmed-7414122 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-74141222020-08-10 Myeloid-derived suppressor cell depletion therapy targets IL-17A-expressing mammary carcinomas Dawod, Bassel Liu, Jinghua Gebremeskel, Simon Yan, Chi Sappong, Antonia Johnston, Brent Hoskin, David W. Marshall, Jean S. Wang, Jun Sci Rep Article Triple-negative breast cancer (TNBC) is an invasive subtype of breast cancer but paradoxically associated with increased tumor-infiltrating leukocytes. The molecular and cellular mechanisms underlying TNBC immunobiology are incompletely understood. Interleukin (IL)-17A is a pro-inflammatory cytokine that has both pro- and anti-tumor effects and found in 40–80% of TNBC samples. We report here that IL-17A mRNA and protein are detectable in some human TNBC cell lines and further upregulated by IL-23 and LPS stimulation. Furthermore, the impact of tumor-derived IL-17A in host immune response and tumor growth was examined using murine TNBC 4T1 mammary carcinoma cells transduced with an adenoviral vector expressing IL-17A (AdIL-17A) or control vector (Addl). Compared to Addl-transduction, AdIL-17A-transduction enhanced 4T1 tumor growth and lung metastasis in vivo, which was associated with a marked expansion of myeloid-derived suppressor cells (MDSCs). However, AdIL-17A-transduction also induced strong organ-specific and time-dependent immune activation indicated by dynamic changes of NK cells, B cells, CD4, and CD8 T cells in peripheral blood, lung, and tumor site, as well as the plasma levels of IFNγ. Such findings highlight that tumor-associated IL-17A induces concurrent immune activation and immune suppression. Administration of anti-Gr1 or anti-G-CSF antibody effectively depleted MDSCs in vivo, markedly reducing the growth of AdIL-17A-transduced 4T1 tumors, and eliminating lung metastasis. Collectively, our study demonstrates that MDSC depletion is an effective and practical approach for treating IL-17A-enriched mammary carcinomas. Nature Publishing Group UK 2020-08-07 /pmc/articles/PMC7414122/ /pubmed/32770025 http://dx.doi.org/10.1038/s41598-020-70231-7 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Dawod, Bassel Liu, Jinghua Gebremeskel, Simon Yan, Chi Sappong, Antonia Johnston, Brent Hoskin, David W. Marshall, Jean S. Wang, Jun Myeloid-derived suppressor cell depletion therapy targets IL-17A-expressing mammary carcinomas |
title | Myeloid-derived suppressor cell depletion therapy targets IL-17A-expressing mammary carcinomas |
title_full | Myeloid-derived suppressor cell depletion therapy targets IL-17A-expressing mammary carcinomas |
title_fullStr | Myeloid-derived suppressor cell depletion therapy targets IL-17A-expressing mammary carcinomas |
title_full_unstemmed | Myeloid-derived suppressor cell depletion therapy targets IL-17A-expressing mammary carcinomas |
title_short | Myeloid-derived suppressor cell depletion therapy targets IL-17A-expressing mammary carcinomas |
title_sort | myeloid-derived suppressor cell depletion therapy targets il-17a-expressing mammary carcinomas |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414122/ https://www.ncbi.nlm.nih.gov/pubmed/32770025 http://dx.doi.org/10.1038/s41598-020-70231-7 |
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