TGF-β Alters the Proportion of Infiltrating Immune Cells in a Pancreatic Ductal Adenocarcinoma.
PD-L1
PDAC
Pancreatic cancer
TAMs
TGF-β
Tumor-associated macrophages
Journal
Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract
ISSN: 1873-4626
Titre abrégé: J Gastrointest Surg
Pays: United States
ID NLM: 9706084
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
10
11
2020
accepted:
27
06
2021
pubmed:
15
7
2021
medline:
27
1
2022
entrez:
14
7
2021
Statut:
ppublish
Résumé
Immunotherapy, such as checkpoint inhibitors against anti-programmed death-ligand 1 (PD-L1), has not been successful in treating patients with pancreatic ductal adenocarcinoma (PDAC). Tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), and the TGF-β cytokine are critical in anti-cancer immunity. We hypothesized that TGF-β enhances the immunosuppressive effects of TAM, MDSC, and DC presence in tumors. Using a murine PDAC cell line derived from a genetically engineered mouse model, we orthotopically implanted treated cells plus drug embedded in Matrigel into immunocompetent mice. Treatments included saline control, TGF-β1, or a TGF-β receptor 1 small molecule inhibitor, galunisertib. We investigated TAM, MDSC, DC, and TAM PD-L1 expression with flow cytometry in tumors. Separately, we used the TIMER2.0 database to analyze TAM and PD-L1 gene expression in human PDAC tumors in TCGA database. TGF-β did not alter MDSC or DC frequencies in the primary tumors. However, in PDAC metastases to the liver, TGF-β decreased the proportion of MDSCs (P=0.022) and DCs (P=0.005). TGF-β significantly increased the percent of high PD-L1 expressing TAMs (32 ± 6 % vs. 12 ± 5%, P=0.013) but not the proportion of TAMs in primary and metastatic tumors. TAM PD-L1 gene expression in TCGA PDAC database was significantly correlated with tgb1 and tgfbr1 gene expression (P<0.01). TGF-β is important in PDAC anti-tumor immunity, demonstrating context-dependent impact on immune cells. TGF-β has an overall immunosuppressive effect mediated by TAM PD-L1 expression and decreased presence of DCs. Future investigations will focus on enhancing anti-cancer immune effects of TGF-β receptor inhibition.
Identifiants
pubmed: 34260016
doi: 10.1007/s11605-021-05087-x
pii: 10.1007/s11605-021-05087-x
doi:
Substances chimiques
B7-H1 Antigen
0
Cd274 protein, mouse
0
Transforming Growth Factor beta
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
113-121Subventions
Organisme : NCI NIH HHS
ID : F31 CA268871
Pays : United States
Informations de copyright
© 2021. The Society for Surgery of the Alimentary Tract.
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