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

Sebastian R. Nielsen*, Jan E. Strøbech, Edward R. Horton, Rene Jackstadt, Anu Laitala, Marina C. Bravo, Giorgia Maltese, Adina R.D. Jensen, Raphael Reuten, Maria Rafaeva, Saadia A. Karim, Chang Il Hwang, Luis Arnes, David A. Tuveson, Owen J. Sansom, Jennifer P. Morton, Janine T. Erler

*Corresponding author af dette arbejde

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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.

OriginalsprogEngelsk
Artikelnummer3414
TidsskriftNature Communications
Vol/bind12
Udgave nummer1
Sider (fra-til)1-15
ISSN2041-1723
DOI
StatusUdgivet - dec. 2021

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© 2021, The Author(s).

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