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...

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Vydáno v:	Nature communications Ročník 12; číslo 1; s. 3414 - 15
Hlavní autoři:	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.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 07.06.2021 Nature Publishing Group Nature Portfolio
Témata:	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
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Shrnutí:	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.
Bibliografie:	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