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

Bellomo, G, Rainer, C, Quaranta, V, Astuti, Y, Raymant, M, Boyd, E, Stafferton, R, Campbell, F, Ghaneh, P, Halloran, CM, Hammond, DE ORCID: 0000-0002-6326-8739, Morton, JP, Palmer, D, Vimalachandran, D, Jones, R, Mielgo, A and Schmid, MC ORCID: 0000-0002-3445-0013 (2022) Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. Gut, 71 (11). pp. 2284-2299. ISSN 0017-5749

Preview

Text Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6AXL signalling axis.pdf - Published Version Available under License Creative Commons Attribution. Download (13MB) | Preview

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:	Article
Uncontrolled Keywords:	Neutrophils; Animals; Humans; Mice; Carcinoma, Pancreatic Ductal; Liver Neoplasms; Pancreatic Neoplasms; Neoplasm Metastasis; Disease Progression; Receptor Protein-Tyrosine Kinases; Intercellular Signaling Peptides and Proteins; Proto-Oncogene Proteins; Antineoplastic Agents; Tumor Microenvironment; immune response; liver metastases; macrophages; pancreatic cancer; Animals; Antineoplastic Agents; Carcinoma, Pancreatic Ductal; Disease Progression; Humans; Intercellular Signaling Peptides and Proteins; Liver Neoplasms; Mice; Neoplasm Metastasis; Neutrophils; Pancreatic Neoplasms; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Tumor Microenvironment; 32 Biomedical and Clinical Sciences; 3211 Oncology and Carcinogenesis; 3204 Immunology; Rare Diseases; Digestive Diseases; Liver Disease; Pancreatic Cancer; Orphan Drug; Cancer; 2.1 Biological and endogenous factors; 5.1 Pharmaceuticals; Cancer; 3 Good Health and Well Being; Animals; Antineoplastic Agents; Carcinoma, Pancreatic Ductal; Disease Progression; Humans; Intercellular Signaling Peptides and Proteins; Liver Neoplasms; Mice; Neoplasm Metastasis; Neutrophils; Pancreatic Neoplasms; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Tumor Microenvironment; 1103 Clinical Sciences; 1114 Paediatrics and Reproductive Medicine; Gastroenterology & Hepatology; 3202 Clinical sciences; 3210 Nutrition and dietetics
Subjects:	Q Science > QD Chemistry Q Science > QH Natural history > QH301 Biology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions:	Pharmacy and Biomolecular Sciences
Publisher:	BMJ
Date of acceptance:	19 December 2021
Date of first compliant Open Access:	7 July 2026
Date Deposited:	07 Jul 2026 10:12
Last Modified:	07 Jul 2026 10:12
DOI or ID number:	10.1136/gutjnl-2021-325272
URI:	https://researchonline.ljmu.ac.uk/id/eprint/28967

View Item