After showing that CSF1R expression in human pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis, Candido et al. inhibited CSF1R phosphorylation in mice with pancreatic cancer using the small molecule AZD7507. AZD7507 monotherapy led to the depletion of CSF1R+PD-L1+ tumor-associated macrophages, looser stroma, reduction in pro-tumor cytokines and chemokines, increased infiltration of CD8+ and CD4+ T cells (but not Tregs), reduced tumor mass, and prolonged survival. AZD7507 altered the PDAC gene expression away from the squamous subtype, which is associated with poor outcome.
Pancreatic 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.
