Pam2 lipopeptides systemically increase myeloid-derived suppressor cells through TLR2 signaling.

Abstract

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that exhibit potent immunosuppressive activity. They are increased in tumor-bearing hosts and contribute to tumor development. Toll-like receptors (TLRs) on MDSCs may modulate the tumor-supporting properties of MDSCs through pattern-recognition. Pam2 lipopeptides represented by Pam2CSK4 serve as a TLR2 agonist to exert anti-tumor function by dendritic cell (DC)-priming that leads to NK cell activation and cytotoxic T cell proliferation. On the other hand, TLR2 enhances tumor cell progression/invasion by activating tumor-infiltrating macrophages. How MDSCs respond to TLR2 agonists has not yet been determined. In this study, we found intravenous administration of Pam2CSK4 systemically up-regulated the frequency of MDSCs in EG7 tumor-bearing mice. The frequency of tumor-infiltrating MDSCs was accordingly increased in response to Pam2CSK4. MDSCs were not increased by Pam2CSK4 stimuli in TLR2 knockout (KO) mice. Adoptive transfer experiments using CFSE-labeled MDSCs revealed that the TLR2-positive MDSCs survived long in tumor-bearing mice in response to Pam2CSK4 treatment. Since the increased MDSC population sustained immune-suppressive properties, our study suggests that Pam2CSK4-triggered TLR2 activation enhances the MDSC potential and suppress antitumor immune response in tumor microenvironment.

• Authors: Akira Maruyama, Hiroaki Shime, Yohei Takeda, Masahiro Azuma, Misako Matsumoto, Tsukasa Seya
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 457 Issue 3 Pg. 445-50 (Feb 13 2015) ISSN: 1090-2104 [Electronic] United States
• PMID: 25596131 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Ligands
• Lipopeptides
• Pam2CSK4 lipopeptide
• Tlr2 protein, mouse
• Toll-Like Receptor 2

Topics

• Animals
• Cell Line, Tumor
• Cell Survival (drug effects)
• Female
• Immunotherapy
• Ligands
• Lipopeptides (immunology, metabolism, pharmacology)
• Lymphoma (immunology, metabolism, therapy)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Myeloid Cells (drug effects, immunology, metabolism)
• Signal Transduction (drug effects)
• Toll-Like Receptor 2 (deficiency, genetics, metabolism)
• Tumor Microenvironment