Myeloid-derived suppressor cell inhibition of the IFN response in tumor-bearing mice

Cancer Res. 2011 Aug 1;71(15):5101-10. doi: 10.1158/0008-5472.CAN-10-2670. Epub 2011 Jun 16.

Abstract

Our group and others have determined that immune effector cells from patients with advanced cancers exhibit reduced activation of IFN signaling pathways. We hypothesized that increases in immune regulatory cells termed myeloid-derived suppressor cells (MDSC) could interfere with the host immune response to tumors by inhibiting immune cell responsiveness to IFNs. The C26 murine adenocarcinoma model was employed to study immune function in advanced malignancy. C26-bearing mice had significantly elevated levels of GR1(+)CD11b(+) MDSC as compared with control mice, and splenocytes from tumor-bearing mice exhibited reduced phosphorylation of STAT1 (P-STAT1) on Tyr(701) in response to IFN-α or IFN-γ. This inhibition was seen in splenic CD4(+) and CD8(+) T cells as well as natural killer cells. In vitro coculture experiments revealed that MDSC inhibited the IFN responsiveness of splenocytes from normal mice. Treatment of C26-bearing mice with gemcitabine or an anti-GR1 antibody led to depletion of MDSC and restored splenocyte IFN responsiveness. Spleens from C26-bearing animals displayed elevated levels of iNOS protein and nitric oxide. In vitro treatment of splenocytes with a nitric oxide donor led to a decreased STAT1 IFN response. The elevation in nitric oxide in C26-bearing mice was associated with increased levels of nitration on STAT1. Finally, splenocytes from iNOS knockout mice bearing C26 tumors exhibited a significantly elevated IFN response as compared with control C26 tumor-bearing mice. These data suggest that nitric oxide produced by MDSC can lead to reduced IFN responsiveness in immune cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / immunology*
  • Adenocarcinoma / pathology
  • Animals
  • CD11b Antigen / analysis
  • Coculture Techniques
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / immunology*
  • Colonic Neoplasms / pathology
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / therapeutic use
  • Female
  • Interferon Type I / pharmacology
  • Interferon-gamma / pharmacology
  • Interferons / antagonists & inhibitors*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred DBA
  • Mice, Knockout
  • Myeloid Cells / physiology*
  • Neoplasm Proteins / metabolism
  • Nitric Oxide / metabolism
  • Nitric Oxide Donors / pharmacology
  • Nitric Oxide Synthase Type II / analysis
  • Nitric Oxide Synthase Type II / deficiency
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Receptors, Cell Surface / analysis
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / immunology
  • Receptors, Interferon
  • Recombinant Proteins
  • STAT1 Transcription Factor / metabolism
  • Spleen / enzymology
  • Spleen / pathology
  • Tumor Escape / immunology*

Substances

  • CD11b Antigen
  • Interferon Type I
  • Neoplasm Proteins
  • Nitric Oxide Donors
  • Receptors, Cell Surface
  • Receptors, Interferon
  • Recombinant Proteins
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • granulocyte receptor 1, mouse
  • interferon gamma receptor
  • Deoxycytidine
  • Nitric Oxide
  • Interferon-gamma
  • Interferons
  • gemcitabine
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse