气体6
转移
癌症研究
医学
肿瘤微环境
化疗
胰腺癌
病理
癌症
内科学
受体
受体酪氨酸激酶
肿瘤细胞
作者
Gaia Bellomo,Carolyn Rainer,Valeria Quaranta,Yuliana Astuti,Meirion Raymant,Elzbieta Boyd,Ruth Stafferton,Fiona Campbell,Paula Ghaneh,Christopher Halloran,Dean E. Hammond,Jennifer P. Morton,Daniel Palmer,Dale Vimalachandran,Robert Jones,Ainhoa Mielgo,Michael C. Schmid
出处
期刊:Gut
[BMJ]
日期:2022-01-12
卷期号:71 (11): 2284-2299
被引量:33
标识
DOI:10.1136/gutjnl-2021-325272
摘要
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.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.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.Combining chemotherapy with Gas6/AXL or neutrophil targeted therapy could provide a therapeutic benefit for patients with metastatic pancreatic cancer.
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