Cargando…

The Tumor Milieu Promotes Functional Human Tumor-Resident Plasmacytoid Dendritic Cells in Humanized Mouse Models

Particular interest to harness the innate immune system for cancer immunotherapy is fueled by limitations of immune checkpoint blockade. Plasmacytoid dendritic cells (pDC) are detected in a variety of solid tumors and correlate with poor clinical outcome. Release of type I interferons in response to...

Descripción completa

Detalles Bibliográficos
Autores principales: Maser, Ilona-Petra, Hoves, Sabine, Bayer, Christa, Heidkamp, Gordon, Nimmerjahn, Falk, Eckmann, Jan, Ries, Carola H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507800/
https://www.ncbi.nlm.nih.gov/pubmed/33013879
http://dx.doi.org/10.3389/fimmu.2020.02082
_version_ 1783585302434021376
author Maser, Ilona-Petra
Hoves, Sabine
Bayer, Christa
Heidkamp, Gordon
Nimmerjahn, Falk
Eckmann, Jan
Ries, Carola H.
author_facet Maser, Ilona-Petra
Hoves, Sabine
Bayer, Christa
Heidkamp, Gordon
Nimmerjahn, Falk
Eckmann, Jan
Ries, Carola H.
author_sort Maser, Ilona-Petra
collection PubMed
description Particular interest to harness the innate immune system for cancer immunotherapy is fueled by limitations of immune checkpoint blockade. Plasmacytoid dendritic cells (pDC) are detected in a variety of solid tumors and correlate with poor clinical outcome. Release of type I interferons in response to toll-like-receptor (TLR)7 and TLR9 activation is the pDC hallmark. Mouse and human pDC differ substantially in their biology concerning surface marker expression and cytokine production. Here, we employed humanized mouse models (HIS) to study pDC function. We performed a comprehensive characterization of transgenic, myeloid-enhanced mouse strains (NOG-EXL and NSG-SGM3) expressing human interleukin-3 (hIL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF) using identical humanization protocols. Only in HIS-NOG-EXL mice sufficient pDC infiltration was detectable. Therefore, we selected this strain for subsequent tumor studies. We analyzed pDC frequency in peripheral blood and tumors by comparing HIS-NOG-EXL with HIS-NOG mice bearing three different ovarian and breast tumors. Despite the substantially increased pDC numbers in peripheral blood of HIS-NOG-EXL mice, we detected TLR7/8 agonist responsive and thus functional pDCs only in certain tumor models independent of the mouse strain employed. However, HIS-NOG-EXL mice showed in general a superior humanization phenotype characterized by reconstitution of different myeloid subsets, NK cells and B cells producing physiologic IgG levels. Hence, we provide first evidence that the tumor milieu but not genetically introduced cytokines defines intratumoral (i.t.) frequencies of the rare pDC subset. This study provides model systems to investigate in vivo pro- and anti-tumoral human pDC functions.
format Online
Article
Text
id pubmed-7507800
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-75078002020-10-02 The Tumor Milieu Promotes Functional Human Tumor-Resident Plasmacytoid Dendritic Cells in Humanized Mouse Models Maser, Ilona-Petra Hoves, Sabine Bayer, Christa Heidkamp, Gordon Nimmerjahn, Falk Eckmann, Jan Ries, Carola H. Front Immunol Immunology Particular interest to harness the innate immune system for cancer immunotherapy is fueled by limitations of immune checkpoint blockade. Plasmacytoid dendritic cells (pDC) are detected in a variety of solid tumors and correlate with poor clinical outcome. Release of type I interferons in response to toll-like-receptor (TLR)7 and TLR9 activation is the pDC hallmark. Mouse and human pDC differ substantially in their biology concerning surface marker expression and cytokine production. Here, we employed humanized mouse models (HIS) to study pDC function. We performed a comprehensive characterization of transgenic, myeloid-enhanced mouse strains (NOG-EXL and NSG-SGM3) expressing human interleukin-3 (hIL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF) using identical humanization protocols. Only in HIS-NOG-EXL mice sufficient pDC infiltration was detectable. Therefore, we selected this strain for subsequent tumor studies. We analyzed pDC frequency in peripheral blood and tumors by comparing HIS-NOG-EXL with HIS-NOG mice bearing three different ovarian and breast tumors. Despite the substantially increased pDC numbers in peripheral blood of HIS-NOG-EXL mice, we detected TLR7/8 agonist responsive and thus functional pDCs only in certain tumor models independent of the mouse strain employed. However, HIS-NOG-EXL mice showed in general a superior humanization phenotype characterized by reconstitution of different myeloid subsets, NK cells and B cells producing physiologic IgG levels. Hence, we provide first evidence that the tumor milieu but not genetically introduced cytokines defines intratumoral (i.t.) frequencies of the rare pDC subset. This study provides model systems to investigate in vivo pro- and anti-tumoral human pDC functions. Frontiers Media S.A. 2020-09-08 /pmc/articles/PMC7507800/ /pubmed/33013879 http://dx.doi.org/10.3389/fimmu.2020.02082 Text en Copyright © 2020 Maser, Hoves, Bayer, Heidkamp, Nimmerjahn, Eckmann and Ries. http://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
Maser, Ilona-Petra
Hoves, Sabine
Bayer, Christa
Heidkamp, Gordon
Nimmerjahn, Falk
Eckmann, Jan
Ries, Carola H.
The Tumor Milieu Promotes Functional Human Tumor-Resident Plasmacytoid Dendritic Cells in Humanized Mouse Models
title The Tumor Milieu Promotes Functional Human Tumor-Resident Plasmacytoid Dendritic Cells in Humanized Mouse Models
title_full The Tumor Milieu Promotes Functional Human Tumor-Resident Plasmacytoid Dendritic Cells in Humanized Mouse Models
title_fullStr The Tumor Milieu Promotes Functional Human Tumor-Resident Plasmacytoid Dendritic Cells in Humanized Mouse Models
title_full_unstemmed The Tumor Milieu Promotes Functional Human Tumor-Resident Plasmacytoid Dendritic Cells in Humanized Mouse Models
title_short The Tumor Milieu Promotes Functional Human Tumor-Resident Plasmacytoid Dendritic Cells in Humanized Mouse Models
title_sort tumor milieu promotes functional human tumor-resident plasmacytoid dendritic cells in humanized mouse models
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507800/
https://www.ncbi.nlm.nih.gov/pubmed/33013879
http://dx.doi.org/10.3389/fimmu.2020.02082
work_keys_str_mv AT maserilonapetra thetumormilieupromotesfunctionalhumantumorresidentplasmacytoiddendriticcellsinhumanizedmousemodels
AT hovessabine thetumormilieupromotesfunctionalhumantumorresidentplasmacytoiddendriticcellsinhumanizedmousemodels
AT bayerchrista thetumormilieupromotesfunctionalhumantumorresidentplasmacytoiddendriticcellsinhumanizedmousemodels
AT heidkampgordon thetumormilieupromotesfunctionalhumantumorresidentplasmacytoiddendriticcellsinhumanizedmousemodels
AT nimmerjahnfalk thetumormilieupromotesfunctionalhumantumorresidentplasmacytoiddendriticcellsinhumanizedmousemodels
AT eckmannjan thetumormilieupromotesfunctionalhumantumorresidentplasmacytoiddendriticcellsinhumanizedmousemodels
AT riescarolah thetumormilieupromotesfunctionalhumantumorresidentplasmacytoiddendriticcellsinhumanizedmousemodels
AT maserilonapetra tumormilieupromotesfunctionalhumantumorresidentplasmacytoiddendriticcellsinhumanizedmousemodels
AT hovessabine tumormilieupromotesfunctionalhumantumorresidentplasmacytoiddendriticcellsinhumanizedmousemodels
AT bayerchrista tumormilieupromotesfunctionalhumantumorresidentplasmacytoiddendriticcellsinhumanizedmousemodels
AT heidkampgordon tumormilieupromotesfunctionalhumantumorresidentplasmacytoiddendriticcellsinhumanizedmousemodels
AT nimmerjahnfalk tumormilieupromotesfunctionalhumantumorresidentplasmacytoiddendriticcellsinhumanizedmousemodels
AT eckmannjan tumormilieupromotesfunctionalhumantumorresidentplasmacytoiddendriticcellsinhumanizedmousemodels
AT riescarolah tumormilieupromotesfunctionalhumantumorresidentplasmacytoiddendriticcellsinhumanizedmousemodels