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IFNAR1 Deficiency Impairs Immunostimulatory Properties of Neutrophils in Tumor-Draining Lymph Nodes

Tumor-draining lymph nodes (TDLNs) are the first organs where the metastatic spread of different types of cancer, including head and neck cancer (HNC), occurs and have therefore high prognostic relevance. Moreover, first anti-cancer immune responses have been shown to be initiated in such LNs via tu...

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Autores principales: Hussain, Timon, Domnich, Maksim, Bordbari, Sharareh, Pylaeva, Ekaterina, Siakaeva, Elena, Spyra, Ilona, Ozel, Irem, Droege, Freya, Squire, Anthony, Lienenklaus, Stefan, Sutter, Kathrin, Hasenberg, Anja, Gunzer, Matthias, Lang, Stephan, Jablonska, Jadwiga
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9271705/
https://www.ncbi.nlm.nih.gov/pubmed/35833131
http://dx.doi.org/10.3389/fimmu.2022.878959
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author Hussain, Timon
Domnich, Maksim
Bordbari, Sharareh
Pylaeva, Ekaterina
Siakaeva, Elena
Spyra, Ilona
Ozel, Irem
Droege, Freya
Squire, Anthony
Lienenklaus, Stefan
Sutter, Kathrin
Hasenberg, Anja
Gunzer, Matthias
Lang, Stephan
Jablonska, Jadwiga
author_facet Hussain, Timon
Domnich, Maksim
Bordbari, Sharareh
Pylaeva, Ekaterina
Siakaeva, Elena
Spyra, Ilona
Ozel, Irem
Droege, Freya
Squire, Anthony
Lienenklaus, Stefan
Sutter, Kathrin
Hasenberg, Anja
Gunzer, Matthias
Lang, Stephan
Jablonska, Jadwiga
author_sort Hussain, Timon
collection PubMed
description Tumor-draining lymph nodes (TDLNs) are the first organs where the metastatic spread of different types of cancer, including head and neck cancer (HNC), occurs and have therefore high prognostic relevance. Moreover, first anti-cancer immune responses have been shown to be initiated in such LNs via tumor-educated myeloid cells. Among myeloid cells present in TDLNs, neutrophils represent a valuable population and considerably participate in the activation of effector lymphocytes there. Tumor-supportive or tumor-inhibiting activity of neutrophils strongly depends on the surrounding microenvironment. Thus, type I interferon (IFN) availability has been shown to prime anti-tumor activity of these cells. In accordance, mice deficient in type I IFNs show elevated tumor growth and metastatic spread, accompanied by the pro-tumoral neutrophil bias. To reveal the mechanism responsible for this phenomenon, we have studied here the influence of defective type I IFN signaling on the immunoregulatory activity of neutrophils in TDLNs. Live imaging of such LNs was performed using two-photon microscopy in a transplantable murine HNC model. Catchup(IVM-red) and Ifnar1(-/-) (type I IFN receptor- deficient) Catchup(IVM-red) mice were used to visualize neutrophils and to assess their interaction with T-cells in vivo. We have evaluated spatiotemporal patterns of neutrophil/T-cell interactions in LNs in the context of type I interferon receptor (IFNAR1) availability in tumor-free and tumor-bearing animals. Moreover, phenotypic and functional analyses were performed to further characterize the mechanisms regulating neutrophil immunoregulatory capacity. We demonstrated that inactive IFNAR1 leads to elevated accumulation of neutrophils in TDLNs. However, these neutrophils show significantly impaired capacity to interact with and to stimulate T-cells. As a result, a significant reduction of contacts between neutrophils and T lymphocytes is observed, with further impairment of T-cell proliferation and activation. This possibly contributes to the enhanced tumor growth in Ifnar1(-/-) mice. In agreement with this, IFNAR1-independent activation of downstream IFN signaling using IFN-λ improved the immunostimulatory capacity of neutrophils in TDLNs and contributed to the suppression of tumor growth. Our results suggest that functional type I IFN signaling is essential for neutrophil immunostimulatory capacity and that stimulation of this signaling may provide a therapeutic opportunity in head and neck cancer patients.
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spelling pubmed-92717052022-07-12 IFNAR1 Deficiency Impairs Immunostimulatory Properties of Neutrophils in Tumor-Draining Lymph Nodes Hussain, Timon Domnich, Maksim Bordbari, Sharareh Pylaeva, Ekaterina Siakaeva, Elena Spyra, Ilona Ozel, Irem Droege, Freya Squire, Anthony Lienenklaus, Stefan Sutter, Kathrin Hasenberg, Anja Gunzer, Matthias Lang, Stephan Jablonska, Jadwiga Front Immunol Immunology Tumor-draining lymph nodes (TDLNs) are the first organs where the metastatic spread of different types of cancer, including head and neck cancer (HNC), occurs and have therefore high prognostic relevance. Moreover, first anti-cancer immune responses have been shown to be initiated in such LNs via tumor-educated myeloid cells. Among myeloid cells present in TDLNs, neutrophils represent a valuable population and considerably participate in the activation of effector lymphocytes there. Tumor-supportive or tumor-inhibiting activity of neutrophils strongly depends on the surrounding microenvironment. Thus, type I interferon (IFN) availability has been shown to prime anti-tumor activity of these cells. In accordance, mice deficient in type I IFNs show elevated tumor growth and metastatic spread, accompanied by the pro-tumoral neutrophil bias. To reveal the mechanism responsible for this phenomenon, we have studied here the influence of defective type I IFN signaling on the immunoregulatory activity of neutrophils in TDLNs. Live imaging of such LNs was performed using two-photon microscopy in a transplantable murine HNC model. Catchup(IVM-red) and Ifnar1(-/-) (type I IFN receptor- deficient) Catchup(IVM-red) mice were used to visualize neutrophils and to assess their interaction with T-cells in vivo. We have evaluated spatiotemporal patterns of neutrophil/T-cell interactions in LNs in the context of type I interferon receptor (IFNAR1) availability in tumor-free and tumor-bearing animals. Moreover, phenotypic and functional analyses were performed to further characterize the mechanisms regulating neutrophil immunoregulatory capacity. We demonstrated that inactive IFNAR1 leads to elevated accumulation of neutrophils in TDLNs. However, these neutrophils show significantly impaired capacity to interact with and to stimulate T-cells. As a result, a significant reduction of contacts between neutrophils and T lymphocytes is observed, with further impairment of T-cell proliferation and activation. This possibly contributes to the enhanced tumor growth in Ifnar1(-/-) mice. In agreement with this, IFNAR1-independent activation of downstream IFN signaling using IFN-λ improved the immunostimulatory capacity of neutrophils in TDLNs and contributed to the suppression of tumor growth. Our results suggest that functional type I IFN signaling is essential for neutrophil immunostimulatory capacity and that stimulation of this signaling may provide a therapeutic opportunity in head and neck cancer patients. Frontiers Media S.A. 2022-06-27 /pmc/articles/PMC9271705/ /pubmed/35833131 http://dx.doi.org/10.3389/fimmu.2022.878959 Text en Copyright © 2022 Hussain, Domnich, Bordbari, Pylaeva, Siakaeva, Spyra, Ozel, Droege, Squire, Lienenklaus, Sutter, Hasenberg, Gunzer, Lang and Jablonska https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Hussain, Timon
Domnich, Maksim
Bordbari, Sharareh
Pylaeva, Ekaterina
Siakaeva, Elena
Spyra, Ilona
Ozel, Irem
Droege, Freya
Squire, Anthony
Lienenklaus, Stefan
Sutter, Kathrin
Hasenberg, Anja
Gunzer, Matthias
Lang, Stephan
Jablonska, Jadwiga
IFNAR1 Deficiency Impairs Immunostimulatory Properties of Neutrophils in Tumor-Draining Lymph Nodes
title IFNAR1 Deficiency Impairs Immunostimulatory Properties of Neutrophils in Tumor-Draining Lymph Nodes
title_full IFNAR1 Deficiency Impairs Immunostimulatory Properties of Neutrophils in Tumor-Draining Lymph Nodes
title_fullStr IFNAR1 Deficiency Impairs Immunostimulatory Properties of Neutrophils in Tumor-Draining Lymph Nodes
title_full_unstemmed IFNAR1 Deficiency Impairs Immunostimulatory Properties of Neutrophils in Tumor-Draining Lymph Nodes
title_short IFNAR1 Deficiency Impairs Immunostimulatory Properties of Neutrophils in Tumor-Draining Lymph Nodes
title_sort ifnar1 deficiency impairs immunostimulatory properties of neutrophils in tumor-draining lymph nodes
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9271705/
https://www.ncbi.nlm.nih.gov/pubmed/35833131
http://dx.doi.org/10.3389/fimmu.2022.878959
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