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

Abstract

ObjectivePancreatic 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.DesignThe 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.ResultsWe 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.ConclusionCombining chemotherapy with Gas6/AXL or neutrophil targeted therapy could provide a therapeutic benefit for patients with metastatic pancreatic cancer.

Focal adhesion kinase priming in pancreatic cancer, altering biomechanics to improve chemotherapy

“…This desmoplastic reaction is heterogeneous throughout the tumour and alters tissue stiffness in a spatially distinct manner which can also influence tumour cell dissemination [ 11–13 ]. Recent studies in PDAC and other cancers have shown that standard-of-care chemotherapy can have unintentional side effects on the stroma, for example, by triggering a chemotherapy-induced wound or fibrotic reaction leading to enhanced fibrosis and tumour stiffness, which is thought to further protect cancer cells from treatment [ 5 , 6 , 14 , 15 ]. This can lead to a vicious cycle of increased fibrosis and decreased response to standard-of-care chemotherapy [ 5 , 16 ].…”

Comprehensive analysis of the novel omicron receptor AXL in cancers

“…In this study, we found that AXL and its ligand GAS6 were highly expressed in many malignant tumors not only in lung cancer. AXL could bind to GAS6 and activate multiple pathways and participate in multiple processes of tumorigenesis, including regulating tumor cell growth, proliferation, migration, invasion and enhancement angiogenesis, etc [24] . Studies also showed that AXL was associated with resistance in patients to antitumor chemotherapy drugs (such as paclitaxel and cisplatin) or molecularly targeted drugs (such as erlotinib and gefitinib) [25] , [26] , [27] .…”

Neutrophils: Musketeers against immunotherapy

“…Then, neutrophil-derived Gas6 induces AXL Receptor Tyrosine Kinase (AXL) on metastatic tumor cells and finally contributes to metastatic growth in liver. Furthermore, the pharmacological targeting of the Gas6/AXL axis through warfarin in combination with gemcitabine treatment suppresses metastatic relapse ( 76 ). Another latest study has revealed that IL-17-mediated neutrophil infiltration contributes to gastric tumor angiogenesis and maintains tumor persistence ( 77 ).…”