CSF1R+ Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype

Cell Rep. 2018 May 1;23(5):1448-1460. doi: 10.1016/j.celrep.2018.03.131.

Abstract

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.

Keywords: CSF1R; T cells; macrophages; pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aniline Compounds / pharmacology
  • Animals
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / immunology*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Female
  • Heterocyclic Compounds, 2-Ring / pharmacology
  • Humans
  • Immunity, Cellular / drug effects
  • Immunity, Cellular / genetics
  • Macrophages / immunology*
  • Macrophages / pathology
  • Male
  • Mice
  • Models, Immunological*
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology*
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / pathology
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / immunology*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology
  • Xenograft Model Antitumor Assays

Substances

  • AZD7507
  • Aniline Compounds
  • CSF1R protein, human
  • Heterocyclic Compounds, 2-Ring
  • Neoplasm Proteins
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor