RESUMEN
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.
Asunto(s)
Antineoplásicos , Carcinoma Ductal Pancreático , Neoplasias Hepáticas , Neoplasias Pancreáticas , Animales , Antineoplásicos/uso terapéutico , Carcinoma Ductal Pancreático/patología , Progresión de la Enfermedad , Humanos , Péptidos y Proteínas de Señalización Intercelular , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Ratones , Metástasis de la Neoplasia , Neutrófilos/metabolismo , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease, yet effective treatments to inhibit PDAC metastasis are lacking. The rich PDAC tumor microenvironment plays a major role in disease progression. Macrophages are the most abundant immune cell population in PDAC tumors and can acquire a range of functions that either hinder or promote tumor growth and metastasis. Here, we identified that mesothelin secretion by pancreatic cancer cells co-opts macrophages to support tumor growth and metastasis of cancer cells to the lungs, liver, and lymph nodes. Mechanistically, secretion of high levels of mesothelin by metastatic cancer cells induced the expression of VEGF alpha (VEGFA) and S100A9 in macrophages. Macrophage-derived VEGFA fed back to cancer cells to support tumor growth, and S100A9 increased neutrophil lung infiltration and formation of neutrophil extracellular traps. These results reveal a role for mesothelin in regulating macrophage functions and interaction with neutrophils to support PDAC metastasis. SIGNIFICANCE: Mesothelin secretion by cancer cells supports pancreatic cancer metastasis by inducing macrophage secretion of VEGFA and S100A9 to support cancer cell proliferation and survival, recruit neutrophils, and stimulate neutrophil extracellular trap formation. See related commentary by Alewine, p. 513.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Mesotelina , Línea Celular Tumoral , Neoplasias Pancreáticas/patología , Macrófagos/metabolismo , Carcinoma Ductal Pancreático/patología , Microambiente Tumoral/fisiologíaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with an urgent unmet clinical need for new therapies. Using a combination of in vitro assays and in vivo preclinical models we demonstrate that therapeutic inhibition of the IGF signalling axis promotes the accumulation of CD8+ cytotoxic T cells within the tumour microenvironment of PDAC tumours. Mechanistically, we show that IGF blockade promotes macrophage and fibroblast production of the chemokines CXCL9 and CXCL10 to facilitate CD8+ T cell recruitment and trafficking towards the PDAC tumour. Exploring this pathway further, we show that IGF inhibition leads to increased STAT1 transcriptional activity, correlating with a downregulation of the AKT/STAT3 signalling axis, in turn promoting Cxcl9 and Cxcl10 gene transcription. Using patient derived tumour explants, we also demonstrate that our findings translate into the human setting. PDAC tumours are frequently described as "immunologically cold", therefore bolstering CD8+ T cell recruitment to PDAC tumours through IGF inhibition may serve to improve the efficacy of immune checkpoint inhibitors which rely on the presence of CD8+ T cells in tumours.
Asunto(s)
Carcinoma Ductal Pancreático , Quimiocina CXCL10 , Quimiocina CXCL9 , Macrófagos , Neoplasias Pancreáticas , Microambiente Tumoral , Quimiocina CXCL9/metabolismo , Humanos , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Animales , Microambiente Tumoral/inmunología , Quimiocina CXCL10/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Ratones , Somatomedinas/metabolismo , Línea Celular Tumoral , Linfocitos T Citotóxicos/inmunología , Factor de Transcripción STAT1/metabolismo , Linfocitos T CD8-positivos/inmunología , Transducción de Señal , Fibroblastos/metabolismo , Fibroblastos/inmunología , Péptidos Similares a la InsulinaRESUMEN
Bile acid malabsorption (BAM) is never life threatening but can cause chronic symptoms. A survey of senior British gastroenterologists was conducted to examine their approach to patients with potential BAM. Of the 706 gastroenterologists contacted, 62% replied. Gastroenterologists see on average 500 new patients in clinic annually; 34% have chronic diarrhoea and 1% are diagnosed with BAM. In those with chronic diarrhoea, 6% of gastroenterologists investigate for BAM first line, while 61% consider the diagnosis only in selected patients or not at all. Sixty-one per cent of patients are diagnosed with type 1 BAM (secondary to terminal ileal disease), 22% have type 2 (idiopathic bile acid malabsorption) and 15% type 3 (unrelated to terminal ileal disease). Only one third of gastroenterologists use a definitive diagnostic test for BAM. BAM (particularly type 2) is under-diagnosed because it is frequently not considered and even when considered, many patients are not subjected to definitive diagnostic testing.