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Cell Rep. 2015 Oct 13;13(2):412-24. doi: 10.1016/j.celrep.2015.08.077. Epub 2015 Sep 24.

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

Author information

1
Swim Across America/Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Swim Across America/Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Cancer Center and Department of Pediatrics, Georgia Regents University, Augusta, GA 30912, USA.
4
Department of Immunology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Swim Across America/Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Immunology and Microbial Pathogenesis Programs, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA. Electronic address: wolchokj@mskcc.org.

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.

PMID:
26411680
PMCID:
PMC5013825
DOI:
10.1016/j.celrep.2015.08.077
[Indexed for MEDLINE]
Free PMC Article

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