Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminopyridines
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology
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Carcinoma, Pancreatic Ductal / drug therapy*
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Carcinoma, Pancreatic Ductal / pathology
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Cell Line, Tumor / transplantation
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Disease Models, Animal
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Drug Synergism
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Female
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Humans
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Immune Checkpoint Inhibitors / pharmacology*
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Immune Checkpoint Inhibitors / therapeutic use
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Lactams
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Lactams, Macrocyclic / pharmacology*
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Lactams, Macrocyclic / therapeutic use
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Lymphocyte Activation / drug effects
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Lymphocytes, Tumor-Infiltrating / drug effects
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Lymphocytes, Tumor-Infiltrating / immunology
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Male
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Mice
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Mice, Transgenic
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Neutrophils / drug effects*
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Neutrophils / immunology
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Pancreatic Neoplasms / drug therapy*
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / immunology
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Pancreatic Neoplasms / pathology
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Programmed Cell Death 1 Receptor / antagonists & inhibitors
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Programmed Cell Death 1 Receptor / metabolism
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Pyrazoles
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Tumor Microenvironment / drug effects
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Tumor Microenvironment / immunology
Substances
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Aminopyridines
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Immune Checkpoint Inhibitors
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Lactams
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Lactams, Macrocyclic
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Pdcd1 protein, mouse
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Programmed Cell Death 1 Receptor
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Pyrazoles
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lorlatinib