Mammary tumor heterogeneity in the expansion of myeloid-derived suppressor cells

Moses K. Donkor, Elaine Lahue, Traci A. Hoke, Laura R. Shafer, Ugur Coskun, Joyce C. Solheim, Dumrul Gulen, John Bishay, James E. Talmadge

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

The tumor microenvironment is heterogeneous for the expansion and infiltration by myeloid derived suppressor cells (MDSCs) which has been hypothesized to be dependent on tumor burden. We report a relationships between tumor size, MDSCs and T-cells; using four murine mammary tumors to assess tumor growth, infiltration and gene expression. Our analysis of cellular infiltration into tumors and gene expression used collagenase dissociated tumors and density gradient isolation of non-parenchymal cells (NPCs). The frequency of splenic and peripheral blood (PB) MDSCs was tumor dependent resulting in a significantly increased number of MDSCs. The MDSC frequency inversely correlated with the frequency of CD3+ lymphocytes in the spleen, independent of the tumor studied and directly correlated with tumor burden. Tumor growth up-regulated cyclooxygenase-2 (COX-2), vascular endothelial growth factor-A (VEGF-A), granulocyte (G-) and granulocyte-monocyte-colony stimulating factor (GM-CSF), arginase-1 (ARG-1), and nitric oxide synthase-2 (NOS-2) transcription in the tumor and spleens (not VEGF-A). The frequency of splenic MDSCs directly correlated with splenic COX-2, NOS-2, and ARG-1 message levels, while COX-2 and NOS-2 transcript levels inversely correlated with splenic CD3+ cell frequency. COX-2 mRNA levels also directly correlated with the ARG-1 and NOS-2 transcript levels from tumor-infiltrating leukocytic cells, supporting prostaglandin E2 as a regulator of ARG-1 and NOS-2 transcription. In summary, MDSC numbers in the spleen and tumor microenvironment are tumor dependent, directly correlating with tumor size and inversely correlating with T-cell number. MDSCs are also directly associated with VEGF-A and G-CSF transcript levels suggesting multiple mechanisms for MDSC regulation and COX-2, NOS-2 and ARG-1 supporting multiple mechanisms of T-cell suppression.

Original languageEnglish (US)
Pages (from-to)937-948
Number of pages12
JournalInternational Immunopharmacology
Volume9
Issue number7-8
DOIs
StatePublished - Jul 2009

Keywords

  • Dendritic cells
  • Immune suppression
  • MDSCs
  • Mammary tumors
  • T-cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

Fingerprint Dive into the research topics of 'Mammary tumor heterogeneity in the expansion of myeloid-derived suppressor cells'. Together they form a unique fingerprint.

Cite this