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.
Author Info: (1) Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. (2) Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, Unive
Author Info: (1) Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. (2) Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. (3) Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. (4) Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. (5) Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. (6) Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. (7) Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. (8) Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK. (9) Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. (10) Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. (11) Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. (12) Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. (13) Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. (14) Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. (15) Bioscience, Oncology, iMED Biotech Unit, AstraZeneca, Boston, MA, USA. (16) Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. (17) Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. (18) Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. (19) Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. (20) Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK. (21) MedImmune Ltd, Granta Park, Cambridge CB21 6GH, UK. (22) Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. (23) Bioscience, Oncology, iMED Biotech Unit, AstraZeneca, Cambridge, UK. (24) Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK. (25) Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. Electronic address: o.sansom@beatson.gla.ac.uk.
