Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis

Bellomo, G. et al. (2022) Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. Gut, 71(11), pp. 2284-2299. (doi: 10.1136/gutjnl-2021-325272) (PMID:35022267) (PMCID:PMC9554050)

[img] Text
263882.pdf - Published Version
Available under License Creative Commons Attribution.

16MB

Abstract

Objective: Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease and cytotoxic chemotherapy is the standard of care treatment for patients with advanced disease. Here, we investigate how the microenvironment in PDAC liver metastases reacts to chemotherapy and its role in metastatic disease progression post-treatment, an area which is poorly understood. Design: The impact of chemotherapy on metastatic disease progression and immune cell infiltrates was characterised using flow and mass cytometry combined with transcriptional and histopathological analysis in experimental PDAC liver metastases mouse models. Findings were validated in patient derived liver metastases and in an autochthonous PDAC mouse model. Human and murine primary cell cocultures and ex vivo patient-derived liver explants were deployed to gain mechanistical insights on whether and how chemotherapy affects the metastatic tumour microenvironment. Results: We show that in vivo, chemotherapy induces an initial infiltration of proinflammatory macrophages into the liver and activates cytotoxic T cells, leading only to a temporary restraining of metastatic disease progression. However, after stopping treatment, neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth. Disruption of neutrophil infiltration or inhibition of the Gas6/AXL signalling axis in combination with chemotherapy inhibits metastatic growth. Chemotherapy increases Gas6 expression in circulating neutrophils from patients with metastatic pancreatic cancer and recombinant Gas6 is sufficient to promote tumour cell proliferation ex vivo, in patient-derived metastatic liver explants. Conclusion: Combining chemotherapy with Gas6/AXL or neutrophil targeted therapy could provide a therapeutic benefit for patients with metastatic pancreatic cancer.

Item Type:Articles
Additional Information:These studies were supported by grants from Cancer Research UK (A25607, A26978, A26979), Medical Research Council (MR/P018920/1) and Pancreatic Cancer Research Fund for MCS, Wellcome Trust (102521/Z/13/Z) and North West Cancer Research Fund for A.M., Cancer Research UK A17196, A2996 and A25233 for JPM.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Morton, Professor Jen
Authors: Bellomo, G., Rainer, C., Quaranta, V., Astuti, Y., Raymant, M., Boyd, E., Stafferton, R., Campbell, F., Ghaneh, P., Halloran, C. M., Hammond, D. E., Morton, J. P., Palmer, D., Vimalachandran, D., Jones, R., Mielgo, A., and Schmid, M. C.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Gut
Publisher:BMJ Publishing Group
ISSN:0017-5749
ISSN (Online):1468-3288
Published Online:12 January 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Gut 71(11): 2284-2299
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record

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