Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer

Cancer Cell. 2012 Jun 12;21(6):822-35. doi: 10.1016/j.ccr.2012.04.025.

Abstract

Cancer-associated inflammation is thought to be a barrier to immune surveillance, particularly in pancreatic ductal adenocarcinoma (PDA). Gr-1(+) CD11b(+) cells are a key feature of cancer inflammation in PDA, but remain poorly understood. Using a genetically engineered mouse model of PDA, we show that tumor-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) is necessary and sufficient to drive the development of Gr-1(+) CD11b(+) cells that suppressed antigen-specific T cells. In vivo, abrogation of tumor-derived GM-CSF inhibited the recruitment of Gr-1(+) CD11b(+) cells to the tumor microenvironment and blocked tumor development-a finding that was dependent on CD8(+) T cells. In humans, PDA tumor cells prominently expressed GM-CSF in vivo. Thus, tumor-derived GM-CSF is an important regulator of inflammation and immune suppression within the tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / immunology*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Animals
  • CD11b Antigen / immunology
  • CD11b Antigen / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Carcinoma, Pancreatic Ductal / immunology*
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology*
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Humans
  • Immunohistochemistry
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Immunological
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism
  • Myeloid Cells / pathology
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • RNA Interference
  • Receptors, Chemokine / immunology
  • Receptors, Chemokine / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Tumor Microenvironment / immunology

Substances

  • CD11b Antigen
  • Gr-1 protein, mouse
  • Receptors, Chemokine
  • Granulocyte-Macrophage Colony-Stimulating Factor