Suppression of tumor-associated neutrophils by lorlatinib attenuates pancreatic cancer growth and improves treatment with immune checkpoint blockade

Pancreatic ductal adenocarcinoma (PDAC) patients have a 5-year survival rate of only 8% largely due to late diagnosis and insufficient therapeutic options. Neutrophils are among the most abundant immune cell type within the PDAC tumor microenvironment (TME), and are associated with a poor clinical p...

Full description

Saved in:
Bibliographic Details
Published in:Nature communications Vol. 12; no. 1; pp. 3414 - 15
Main Authors: Nielsen, Sebastian R., Strøbech, Jan E., Horton, Edward R., Jackstadt, Rene, Laitala, Anu, Bravo, Marina C., Maltese, Giorgia, Jensen, Adina R. D., Reuten, Raphael, Rafaeva, Maria, Karim, Saadia A., Hwang, Chang-Il, Arnes, Luis, Tuveson, David A., Sansom, Owen J., Morton, Jennifer P., Erler, Janine T.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 07.06.2021
Nature Publishing Group
Nature Portfolio
Subjects:
13/106
13/31
13/51
631/67/1504/1713
631/67/327
631/67/580
692/4028/67/580
96/95
Adenocarcinoma
Aminopyridines
Animal models
Animals
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Attenuation
Cancer
Carcinoma, Pancreatic Ductal - drug therapy
Carcinoma, Pancreatic Ductal - pathology
CD8 antigen
CD8-Positive T-Lymphocytes - drug effects
CD8-Positive T-Lymphocytes - immunology
Cell Line, Tumor - transplantation
Disease Models, Animal
Drug Synergism
Enzyme inhibitors
Female
Humanities and Social Sciences
Humans
Immune checkpoint
Immune Checkpoint Inhibitors - pharmacology
Immune Checkpoint Inhibitors - therapeutic use
Immune system
Kinases
Lactams
Lactams, Macrocyclic - pharmacology
Lactams, Macrocyclic - therapeutic use
Leukocytes (neutrophilic)
Lymphocyte Activation - drug effects
Lymphocytes
Lymphocytes T
Lymphocytes, Tumor-Infiltrating - drug effects
Lymphocytes, Tumor-Infiltrating - immunology
Male
Medical prognosis
Mice
Mice, Transgenic
multidisciplinary
Neutrophils
Neutrophils - drug effects
Neutrophils - immunology
Pancreatic cancer
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - immunology
Pancreatic Neoplasms - pathology
Patients
PD-1 protein
Prognosis
Programmed Cell Death 1 Receptor - antagonists & inhibitors
Programmed Cell Death 1 Receptor - metabolism
Protein-tyrosine kinase
Pyrazoles
Science
Science (multidisciplinary)
Survival
Tumor microenvironment
Tumor Microenvironment - drug effects
Tumor Microenvironment - immunology
Tumors
Tyrosine
ISSN:2041-1723, 2041-1723
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Pancreatic ductal adenocarcinoma (PDAC) patients have a 5-year survival rate of only 8% largely due to late diagnosis and insufficient therapeutic options. Neutrophils are among the most abundant immune cell type within the PDAC tumor microenvironment (TME), and are associated with a poor clinical prognosis. However, despite recent advances in understanding neutrophil biology in cancer, therapies targeting tumor-associated neutrophils are lacking. Here, we demonstrate, using pre-clinical mouse models of PDAC, that lorlatinib attenuates PDAC progression by suppressing neutrophil development and mobilization, and by modulating tumor-promoting neutrophil functions within the TME. When combined, lorlatinib also improves the response to anti-PD-1 blockade resulting in more activated CD8 + T cells in PDAC tumors. In summary, this study identifies an effect of lorlatinib in modulating tumor-associated neutrophils, and demonstrates the potential of lorlatinib to treat PDAC. Tumor associated neutrophils have been correlated with poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). Here the authors show that the tyrosine kinase inhibitor lorlatinib modulates neutrophil development and recruitment in the tumor microenvironment, attenuating PDAC progression in preclinical mouse models.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-23731-7