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 > drugs and therapies > lorlatinib organism description > animal > mammal > rodent > mouse diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > drugs and therapies > tumor microenvironment
CSHL Authors:	Tuveson, David A. Hwang, Chang-Il
Communities:	CSHL labs > Tuveson lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	7 June 2021
Date Deposited:	16 Jun 2021 13:26
Last Modified:	16 Jun 2021 13:26
PMCID:	PMC8184753
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/40206

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