Dissecting the Stromal Signaling and Regulation of Myeloid Cells and Memory Effector T Cells in Pancreatic Cancer.
Animals
CD8-Positive T-Lymphocytes
/ drug effects
Cancer Vaccines
/ administration & dosage
Cancer-Associated Fibroblasts
/ drug effects
Carcinoma, Pancreatic Ductal
/ drug therapy
Cell Line, Tumor
Cell Movement
Chemokines
/ immunology
Female
Humans
Immunologic Memory
/ drug effects
Immunosuppression Therapy
Lymphocytes, Tumor-Infiltrating
/ drug effects
Mice
Mice, Inbred C57BL
Mice, Transgenic
Myeloid Cells
/ drug effects
Pancreatic Neoplasms
/ drug therapy
Signal Transduction
Stromal Cells
/ drug effects
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 09 2019
01 09 2019
Historique:
received:
21
12
2018
revised:
01
05
2019
accepted:
06
06
2019
pubmed:
13
6
2019
medline:
18
9
2020
entrez:
13
6
2019
Statut:
ppublish
Résumé
Myeloid cells are a prominent immunosuppressive component within the stroma of pancreatic ductal adenocarcinoma (PDAC). Previously, targeting myeloid cells has had limited success. Here, we sought to target the myeloid cells through modifying a specific stromal component. A murine model of metastatic PDAC treated with an irradiated whole-cell PDAC vaccine and PDAC specimens from patients treated with the same type of vaccine were used to assess the immune-modulating effect of stromal hyaluronan (HA) degradation by PEGPH20. Targeting stroma by degrading HA with PEGPH20 in combination with vaccine decreases CXCL12/CXCR4/CCR7 immunosuppressive signaling axis expression in cancer-associated fibroblasts, myeloid, and CD8 This study represents the first to dissect signaling cascades following PDAC stroma remodeling via HA depletion, suggesting this not only overcomes a physical barrier for immune cell trafficking, but alters myeloid function leading to downstream selective increases in effector memory T-cell infiltration and antitumor activity.
Identifiants
pubmed: 31186314
pii: 1078-0432.CCR-18-4192
doi: 10.1158/1078-0432.CCR-18-4192
pmc: PMC6726532
mid: NIHMS1531776
doi:
Substances chimiques
Cancer Vaccines
0
Chemokines
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5351-5363Subventions
Organisme : NCI NIH HHS
ID : K23 CA148964
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA126607
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA197296
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA169702
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA062924
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA006973
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
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