PGE2-HIF1α reciprocal induction regulates migration, phenotypic alteration and immunosuppressive capacity of macrophages in tumor microenvironment.
Animals
Carcinoma, Ehrlich Tumor
/ immunology
Cell Movement
Dinoprostone
/ metabolism
Disease Progression
Hypoxia-Inducible Factor 1, alpha Subunit
/ metabolism
Inflammation
/ immunology
Macrophages
/ immunology
Male
Mice
Mice, Inbred BALB C
Phenotype
Sarcoma 180
/ immunology
T-Lymphocytes
/ immunology
Tumor Microenvironment
/ immunology
Activated/memory T cell
CD4(+)/CD8(+)
EAC
HIF-1α
IL-10
IL-12
PGE2
S-180
TAM
TIL
TNF-α
Journal
Life sciences
ISSN: 1879-0631
Titre abrégé: Life Sci
Pays: Netherlands
ID NLM: 0375521
Informations de publication
Date de publication:
15 Jul 2020
15 Jul 2020
Historique:
received:
22
10
2019
revised:
27
03
2020
accepted:
24
04
2020
pubmed:
1
5
2020
medline:
11
6
2020
entrez:
1
5
2020
Statut:
ppublish
Résumé
Very little is known about the role inflammation and mechanism(s) that enables the tumor to evade host's anti-tumor immune function during very initial days of tumor establishment. Our study focuses on the immune response and local inflammation specially the pro-inflammatory and immune modifier components that are responsible for tumor-induced immune-suppression, tumor-associated macrophages (TAM) at tumor microenvironment in mouse model from very early to late phase of tumor progression. 1 × 10 We observed increased T cell infiltration at a very early stage of tumorigenesis in the tumor site with elevated percentage of activated/memory T cells. But increased cellular death and functional suppression of tumor site T cells during final stages. We observed increased infiltration of TAMs with skewed M2 phenotype. Increased chemokine receptor expression could be noted on these TAMs. Using HIF-1α inhibitor and prostaglandin receptor antagonists we demonstrated crucial role of these factor in functional alteration in TAMs. HIF-1α inhibition and also by prostaglandin receptor inhibition reduced signature pro-inflammatory gene expression, migration of macrophages and T cell suppression capacity of TAMs. We also demonstrated that PGE2 can induce HIF-1α activation in relatively less hypoxic microenvironment during early stages of tumor. Altogether, these findings strongly suggest link between prostaglandin mediated early HIF-1α activation and subsequent hypoxia induced HIF-1α activation that further enhances prostaglandin synthesis driving the recruitment and functional alteration of tumor site macrophages.
Sections du résumé
BACKGROUND
BACKGROUND
Very little is known about the role inflammation and mechanism(s) that enables the tumor to evade host's anti-tumor immune function during very initial days of tumor establishment. Our study focuses on the immune response and local inflammation specially the pro-inflammatory and immune modifier components that are responsible for tumor-induced immune-suppression, tumor-associated macrophages (TAM) at tumor microenvironment in mouse model from very early to late phase of tumor progression.
METHODS
METHODS
1 × 10
RESULTS
RESULTS
We observed increased T cell infiltration at a very early stage of tumorigenesis in the tumor site with elevated percentage of activated/memory T cells. But increased cellular death and functional suppression of tumor site T cells during final stages. We observed increased infiltration of TAMs with skewed M2 phenotype. Increased chemokine receptor expression could be noted on these TAMs. Using HIF-1α inhibitor and prostaglandin receptor antagonists we demonstrated crucial role of these factor in functional alteration in TAMs. HIF-1α inhibition and also by prostaglandin receptor inhibition reduced signature pro-inflammatory gene expression, migration of macrophages and T cell suppression capacity of TAMs. We also demonstrated that PGE2 can induce HIF-1α activation in relatively less hypoxic microenvironment during early stages of tumor.
CONCLUSION
CONCLUSIONS
Altogether, these findings strongly suggest link between prostaglandin mediated early HIF-1α activation and subsequent hypoxia induced HIF-1α activation that further enhances prostaglandin synthesis driving the recruitment and functional alteration of tumor site macrophages.
Identifiants
pubmed: 32353431
pii: S0024-3205(20)30479-3
doi: 10.1016/j.lfs.2020.117731
pii:
doi:
Substances chimiques
Hif1a protein, mouse
0
Hypoxia-Inducible Factor 1, alpha Subunit
0
Dinoprostone
K7Q1JQR04M
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
117731Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest Authors declare no conflict of interest.