Tumor-Expressed IDO Recruits and Activates MDSCs in a Treg-Dependent Manner.

Abstract

Indoleamine 2,3-dioxygenase (IDO) has been described as a major mechanism of immunosuppression in tumors, though the mechanisms of this are poorly understood. Here, we find that expression of IDO by tumor cells results in aggressive tumor growth and resistance to T-cell-targeting immunotherapies. We demonstrate that IDO orchestrates local and systemic immunosuppressive effects through recruitment and activation of myeloid-derived suppressor cells (MDSCs), through a mechanism dependent on regulatory T cells (Tregs). Supporting these findings, we find that IDO expression in human melanoma tumors is strongly associated with MDSC infiltration. Treatment with a selective IDO inhibitor in vivo reversed tumor-associated immunosuppression by decreasing numbers of tumor-infiltrating MDSCs and Tregs and abolishing their suppressive function. These findings establish an important link between IDO and multiple immunosuppressive mechanisms active in the tumor microenvironment, providing a strong rationale for therapeutic targeting of IDO as one of the central regulators of immune suppression.

• Authors: Rikke B Holmgaard, Dmitriy Zamarin, Yanyun Li, Billel Gasmi, David H Munn, James P Allison, Taha Merghoub, Jedd D Wolchok
• Journal: Cell reports (Cell Rep) Vol. 13 Issue 2 Pg. 412-24 (Oct 13 2015) ISSN: 2211-1247 [Electronic] United States
• PMID: 26411680 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Immunosuppressive Agents
• Indoleamine-Pyrrole 2,3,-Dioxygenase

Topics

• Animals
• Cell Movement
• Cells, Cultured
• Humans
• Immunosuppressive Agents (pharmacology)
• Indoleamine-Pyrrole 2,3,-Dioxygenase (immunology, pharmacology)
• Mice
• Myeloid Cells (drug effects, immunology, physiology)
• Neoplasms (immunology)
• T-Lymphocytes, Regulatory (immunology)