Abstract
SummaryPancreatic ductal adenocarcinoma (PDAC) is resistant to most therapies including single-agent immunotherapy and has a dense desmoplastic stroma, and most patients present with advanced metastatic disease. We reveal that macrophages are the dominant leukocyte population both in human PDAC stroma and autochthonous models, with an important functional contribution to the squamous subtype of human PDAC. We targeted macrophages in a genetic PDAC model using AZD7507, a potent selective inhibitor of CSF1R. AZD7507 caused shrinkage of established tumors and increased mouse survival in this difficult-to-treat model. Malignant cell proliferation diminished, with increased cell death and an enhanced T cell immune response. Loss of macrophages rewired other features of the TME, with global changes in gene expression akin to switching PDAC subtypes. These changes were markedly different to those elicited when neutrophils were targeted via CXCR2. These results suggest targeting the myeloid cell axis may be particularly efficacious in PDAC, especially with CSF1R inhibitors.
Highlights
Pancreatic cancer is predicted to be the second most common cause of cancer death by 2030 (Rahib et al, 2014)
Human and Murine Primary Pancreatic ductal adenocarcinoma (PDAC) Are Infiltrated by colony-stimulating factor-1 receptor (CSF1R)+ Macrophages and Overexpress CSF1 and IL-34 In our previous studies, we found that the macrophage transcriptional signature was high in squamous and immunogenic subtypes of PDAC and that the macrophage transcriptional gene program was associated with a poor prognosis (Bailey et al, 2016)
To determine the presence of macrophages in human PDAC tissues, we used immunohistochemistry (IHC) to stain for CD68, a transmembrane glycoprotein highly expressed by human monocytes and tissue macrophages
Summary
Pancreatic cancer is predicted to be the second most common cause of cancer death by 2030 (Rahib et al, 2014). Over the last 5 years there has been great progress in the understanding of pancreatic cancer (both preclinically and clinically) with numerous innovative trials currently under way. Many of these new developments are based on a deep understanding of the molecular pathology of pancreatic cancer. The definition of subtypes and the use of autochthonous mouse models have allowed modeling of tumor-stroma interaction, and the metastatic process, in immune competent mice (Gopinathan et al, 2015). Several studies in mice have highlighted the importance of the stroma, which provides important pro-survival cues and may impair therapeutic responsiveness (Neesse et al, 2015)
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