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IL-6 regulates CCR5 expression and immunosuppressive capacity of MDSC in murine melanoma

BACKGROUND: Myeloid-derived suppressor cells (MDSC) play a major role in the immunosuppressive melanoma microenvironment. They are generated under chronic inflammatory conditions characterized by the constant production of inflammatory cytokines, chemokines and growth factors, including IL-6. Recrui...

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Autores principales: Weber, Rebekka, Riester, Zeno, Hüser, Laura, Sticht, Carsten, Siebenmorgen, Alina, Groth, Christopher, Hu, Xiaoying, Altevogt, Peter, Utikal, Jochen S, Umansky, Viktor
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422659/
https://www.ncbi.nlm.nih.gov/pubmed/32788238
http://dx.doi.org/10.1136/jitc-2020-000949
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author Weber, Rebekka
Riester, Zeno
Hüser, Laura
Sticht, Carsten
Siebenmorgen, Alina
Groth, Christopher
Hu, Xiaoying
Altevogt, Peter
Utikal, Jochen S
Umansky, Viktor
author_facet Weber, Rebekka
Riester, Zeno
Hüser, Laura
Sticht, Carsten
Siebenmorgen, Alina
Groth, Christopher
Hu, Xiaoying
Altevogt, Peter
Utikal, Jochen S
Umansky, Viktor
author_sort Weber, Rebekka
collection PubMed
description BACKGROUND: Myeloid-derived suppressor cells (MDSC) play a major role in the immunosuppressive melanoma microenvironment. They are generated under chronic inflammatory conditions characterized by the constant production of inflammatory cytokines, chemokines and growth factors, including IL-6. Recruitment of MDSC to the tumor is mediated by the interaction between chemokines and chemokine receptors, in particular C–C chemokine receptor (CCR)5. Here, we studied the mechanisms of CCR5 upregulation and increased immunosuppressive function of CCR5(+) MDSC. METHODS: The immortalized myeloid suppressor cell line MSC-2, primary immature myeloid cells and in vitro differentiated MDSC were used to determine factors and molecular mechanisms regulating CCR5 expression and immunosuppressive markers at the mRNA and protein levels. The relevance of the identified pathways was validated on the RET transgenic mouse melanoma model, which was also used to target the identified pathways in vivo. RESULTS: IL-6 upregulated the expression of CCR5 and arginase 1 in MDSC by a STAT3-dependent mechanism. MDSC differentiated in the presence of IL-6 strongly inhibited CD8(+) T cell functions compared with MDSC differentiated without IL-6. A correlation between IL-6 levels, phosphorylated STAT3 and CCR5 expression in tumor-infiltrating MDSC was demonstrated in the RET transgenic melanoma mouse model. Surprisingly, IL-6 overexpressing tumors grew significantly slower in mice accompanied by CD8(+) T cell activation. Moreover, transgenic melanoma-bearing mice treated with IL-6 blocking antibodies showed significantly accelerated tumor development. CONCLUSION: Our in vitro and ex vivo findings demonstrated that IL-6 induced CCR5 expression and a strong immunosuppressive activity of MDSC, highlighting this cytokine as a promising target for melanoma immunotherapy. However, IL-6 blocking therapy did not prove to be effective in RET transgenic melanoma-bearing mice but rather aggravated tumor progression. Further studies are needed to identify particular combination therapies, cancer entities or patient subsets to benefit from the anti-IL-6 treatment.
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spelling pubmed-74226592020-08-19 IL-6 regulates CCR5 expression and immunosuppressive capacity of MDSC in murine melanoma Weber, Rebekka Riester, Zeno Hüser, Laura Sticht, Carsten Siebenmorgen, Alina Groth, Christopher Hu, Xiaoying Altevogt, Peter Utikal, Jochen S Umansky, Viktor J Immunother Cancer Basic Tumor Immunology BACKGROUND: Myeloid-derived suppressor cells (MDSC) play a major role in the immunosuppressive melanoma microenvironment. They are generated under chronic inflammatory conditions characterized by the constant production of inflammatory cytokines, chemokines and growth factors, including IL-6. Recruitment of MDSC to the tumor is mediated by the interaction between chemokines and chemokine receptors, in particular C–C chemokine receptor (CCR)5. Here, we studied the mechanisms of CCR5 upregulation and increased immunosuppressive function of CCR5(+) MDSC. METHODS: The immortalized myeloid suppressor cell line MSC-2, primary immature myeloid cells and in vitro differentiated MDSC were used to determine factors and molecular mechanisms regulating CCR5 expression and immunosuppressive markers at the mRNA and protein levels. The relevance of the identified pathways was validated on the RET transgenic mouse melanoma model, which was also used to target the identified pathways in vivo. RESULTS: IL-6 upregulated the expression of CCR5 and arginase 1 in MDSC by a STAT3-dependent mechanism. MDSC differentiated in the presence of IL-6 strongly inhibited CD8(+) T cell functions compared with MDSC differentiated without IL-6. A correlation between IL-6 levels, phosphorylated STAT3 and CCR5 expression in tumor-infiltrating MDSC was demonstrated in the RET transgenic melanoma mouse model. Surprisingly, IL-6 overexpressing tumors grew significantly slower in mice accompanied by CD8(+) T cell activation. Moreover, transgenic melanoma-bearing mice treated with IL-6 blocking antibodies showed significantly accelerated tumor development. CONCLUSION: Our in vitro and ex vivo findings demonstrated that IL-6 induced CCR5 expression and a strong immunosuppressive activity of MDSC, highlighting this cytokine as a promising target for melanoma immunotherapy. However, IL-6 blocking therapy did not prove to be effective in RET transgenic melanoma-bearing mice but rather aggravated tumor progression. Further studies are needed to identify particular combination therapies, cancer entities or patient subsets to benefit from the anti-IL-6 treatment. BMJ Publishing Group 2020-08-11 /pmc/articles/PMC7422659/ /pubmed/32788238 http://dx.doi.org/10.1136/jitc-2020-000949 Text en © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Basic Tumor Immunology
Weber, Rebekka
Riester, Zeno
Hüser, Laura
Sticht, Carsten
Siebenmorgen, Alina
Groth, Christopher
Hu, Xiaoying
Altevogt, Peter
Utikal, Jochen S
Umansky, Viktor
IL-6 regulates CCR5 expression and immunosuppressive capacity of MDSC in murine melanoma
title IL-6 regulates CCR5 expression and immunosuppressive capacity of MDSC in murine melanoma
title_full IL-6 regulates CCR5 expression and immunosuppressive capacity of MDSC in murine melanoma
title_fullStr IL-6 regulates CCR5 expression and immunosuppressive capacity of MDSC in murine melanoma
title_full_unstemmed IL-6 regulates CCR5 expression and immunosuppressive capacity of MDSC in murine melanoma
title_short IL-6 regulates CCR5 expression and immunosuppressive capacity of MDSC in murine melanoma
title_sort il-6 regulates ccr5 expression and immunosuppressive capacity of mdsc in murine melanoma
topic Basic Tumor Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422659/
https://www.ncbi.nlm.nih.gov/pubmed/32788238
http://dx.doi.org/10.1136/jitc-2020-000949
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