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

Nielsen, S. R. et al. (2021) Suppression of tumor-associated neutrophils by lorlatinib attenuates pancreatic cancer growth and improves treatment with immune checkpoint blockade. Nature Communications, 12, 3414. (doi: 10.1038/s41467-021-23731-7) (PMID:34099731) (PMCID:PMC8184753)

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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:Articles
Additional Information:This work was supported by the Danish Cancer Society (S.R.N.: R167-A10618; E.R.H.: R204-A12445; R.R.: R204-A12454), the European Molecular Biology Organisation (E.R.H.: ALTF 922-2016), the European Research Council (S.R.N., E.R.H., J.E.S., A.M.L., A.R.D.J., R.R., and J.T.E.: ERC-2015-CoG-682881-Matrican), Cancer Research UK (R.J., S.A.K., J.P.M., and O.J.S.: A25142, A17196, A21139, and A25233), the German Cancer Aid (RR: 9166564), the National Institute of Health (C.I.H.: 1F32CA180717-01A1 and 5K22CA226037-02) and a Hallas-Møller Stipend from the Novo Nordisk Foundation (J.T.E.).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Morton, Professor Jen and Karim, Ms Saadia and Sansom, Professor Owen
Authors: Nielsen, S. R., Strøbech, J. E., Horton, E. R., Jackstadt, R., Laitala, A., Bravo, M. C., Maltese, G., Jensen, A. R. D., Reuten, R., Rafaeva, M., Karim, S. A., Hwang, C.-I., Arnes, L., Tuveson, D. A., Sansom, O. J., Morton, J. P., and Erler, J. T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature Communications
Publisher:Nature Research
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Nature Communications 12: 3414
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
174115CRUK Centre RenewalOwen SansomCancer Research UK (CRUK)C7932/A25142CS - Beatson Institute for Cancer Research
174328Precision-Panc: a dynamic therapeutic development platform for pancreatic cancerOwen SansomCancer Research UK (CRUK)C7932/A25233CS - Beatson Institute for Cancer Research