The Tumor Milieu Promotes Functional Human Tumor-Resident Plasmacytoid Dendritic Cells in Humanized Mouse Models.
Animals
B-Lymphocytes
/ immunology
Carcinoma, Ovarian Epithelial
/ immunology
Cell Line, Tumor
Dendritic Cells
/ immunology
Disease Models, Animal
Female
Granulocyte-Macrophage Colony-Stimulating Factor
/ genetics
Humans
Interleukin-3
/ genetics
Killer Cells, Natural
/ immunology
Mice
Mice, SCID
Mice, Transgenic
Tumor Microenvironment
TLR agonists
cancer immunotherapy
human pDC targeting
humanized mice
myeloid-enhanced mice
plasmacytoid dendritic cells (pDC)
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2020
2020
Historique:
received:
05
03
2020
accepted:
30
07
2020
entrez:
5
10
2020
pubmed:
6
10
2020
medline:
21
5
2021
Statut:
epublish
Résumé
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
Identifiants
pubmed: 33013879
doi: 10.3389/fimmu.2020.02082
pmc: PMC7507800
doi:
Substances chimiques
Interleukin-3
0
Granulocyte-Macrophage Colony-Stimulating Factor
83869-56-1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2082Informations de copyright
Copyright © 2020 Maser, Hoves, Bayer, Heidkamp, Nimmerjahn, Eckmann and Ries.
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