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

Nielsen, Sebastian R, Strøbech, Jan E, Horton, Edward R, Jackstadt, Rene, Laitala, Anu, Bravo, Marina C, Maltese, Giorgia, Jensen, Adina RD, Reuten, Raphael, Rafaeva, Maria, Karim, Saadia A, Hwang, Chang-Il, Arnes, Luis, Tuveson, David A, Sansom, Owen J, Morton, Jennifer P, Erler, Janine T (June 2021) Suppression of tumor-associated neutrophils by lorlatinib attenuates pancreatic cancer growth and improves treatment with immune checkpoint blockade. Nature Communications, 12 (1). p. 3414. ISSN 2041-1723

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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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > neoplasms organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > cancer > drugs and therapies > chemotherapy diseases & disorders > cancer > drugs and therapies diseases & disorders > cancer > drugs and therapies > lorlatinib organs, tissues, organelles, cell types and functions > cell types and functions > cell types > lymphocyte organs, tissues, organelles, cell types and functions > cell types and functions > cell types > lymphocyte organs, tissues, organelles, cell types and functions > cell types and functions > cell types > lymphocyte organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neutrophils organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neutrophils organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neutrophils organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types > pancreatic cancer organism description > animal > mammal > rodent diseases & disorders > cancer > drugs and therapies > tumor microenvironment diseases & disorders > cancer > cancer types
CSHL Authors:	Tuveson, David A. Hwang, Chang-Il
Communities:	CSHL labs > Tuveson lab CSHL Cancer Center Program CSHL Cancer Center Program > Cellular Communication in Cancer Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	7 June 2021
Date Deposited:	16 Jun 2021 13:26
Last Modified:	13 Feb 2024 18:53
PMCID:	PMC8184753
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/40206

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