Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer.
Animals
Biomarkers, Tumor
/ metabolism
CD8-Positive T-Lymphocytes
/ drug effects
Cell Line, Tumor
Drug Resistance, Neoplasm
/ drug effects
Extracellular Traps
/ metabolism
Humans
Immune Checkpoint Inhibitors
/ pharmacology
Immunosuppression Therapy
Interleukin-17
/ pharmacology
Lymphocyte Activation
/ drug effects
Mice, Inbred C57BL
Neutrophils
/ drug effects
Pancreatic Neoplasms
/ drug therapy
Programmed Cell Death 1 Receptor
/ metabolism
Signal Transduction
/ drug effects
Tumor Microenvironment
/ drug effects
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
07 12 2020
07 12 2020
Historique:
received:
24
02
2019
revised:
25
04
2020
accepted:
06
07
2020
entrez:
30
8
2020
pubmed:
30
8
2020
medline:
12
3
2021
Statut:
ppublish
Résumé
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with an immunosuppressive microenvironment that is resistant to most therapies. IL17 is involved in pancreatic tumorigenesis, but its role in invasive PDAC is undetermined. We hypothesized that IL17 triggers and sustains PDAC immunosuppression. We inhibited IL17/IL17RA signaling using pharmacological and genetic strategies alongside mass cytometry and multiplex immunofluorescence techniques. We uncovered that IL17 recruits neutrophils, triggers neutrophil extracellular traps (NETs), and excludes cytotoxic CD8 T cells from tumors. Additionally, IL17 blockade increases immune checkpoint blockade (PD-1, CTLA4) sensitivity. Inhibition of neutrophils or Padi4-dependent NETosis phenocopies IL17 neutralization. NMR spectroscopy revealed changes in tumor lactate as a potential early biomarker for IL17/PD-1 combination efficacy. Higher expression of IL17 and PADI4 in human PDAC corresponds with poorer prognosis, and the serum of patients with PDAC has higher potential for NETosis. Clinical studies with IL17 and checkpoint blockade represent a novel combinatorial therapy with potential efficacy for this lethal disease.
Identifiants
pubmed: 32860704
pii: 152058
doi: 10.1084/jem.20190354
pmc: PMC7953739
pii:
doi:
Substances chimiques
Biomarkers, Tumor
0
Immune Checkpoint Inhibitors
0
Interleukin-17
0
Pdcd1 protein, mouse
0
Programmed Cell Death 1 Receptor
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
Subventions
Organisme : NCI NIH HHS
ID : K12 CA088084
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA237384
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA243707
Pays : United States
Informations de copyright
© 2020 Zhang et al.
Déclaration de conflit d'intérêts
Disclosure: Dr. Maitra reports Thrive Earlier Detection has licensed an invention from Johns Hopkins University in which Dr. Maitra is listed as an inventor. The focus of the license is on pancreatic cancer early detection. In addition, Dr. Maitra receives royalties from Cosmos Wisdom Biotechnology Ltd on an invention related to pancreatic cancer early detection, licensed from MD Anderson Cancer Center. Dr. Banerjee is a paid consultant with Minneamrita Therapeutics; this is managed by the University of Miami. No other disclosures were reported.
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