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 and Janine T. Erler ()
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Sebastian R. Nielsen: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH)
Jan E. Strøbech: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH)
Edward R. Horton: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH)
Rene Jackstadt: CRUK Beatson Institute, Garscube Estate
Anu Laitala: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH)
Marina C. Bravo: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH)
Giorgia Maltese: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH)
Adina R. D. Jensen: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH)
Raphael Reuten: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH)
Maria Rafaeva: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH)
Saadia A. Karim: CRUK Beatson Institute, Garscube Estate
Chang-Il Hwang: Cold Spring Harbor Laboratory, Cold Spring Harbor
Luis Arnes: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH)
David A. Tuveson: Cold Spring Harbor Laboratory, Cold Spring Harbor
Owen J. Sansom: CRUK Beatson Institute, Garscube Estate
Jennifer P. Morton: CRUK Beatson Institute, Garscube Estate
Janine T. Erler: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH)

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23731-7

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