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

Rikke B. Holmgaard, Dmitriy Zamarin, Yanyun Li, Billel Gasmi, David H Munn, James P. Allison, Taha Merghoub, Jedd D. Wolchok

Research output: Contribution to journalArticle

143 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)412-424
Number of pages13
JournalCell Reports
Volume13
Issue number2
DOIs
StatePublished - Oct 13 2015

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Tumors
Neoplasms
T-cells
Immunosuppressive Agents
Immunosuppression
Tumor Microenvironment
Regulatory T-Lymphocytes
Myeloid-Derived Suppressor Cells
Infiltration
Immunotherapy
Melanoma
Chemical activation
Cells
T-Lymphocytes
Therapeutics
Growth

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Holmgaard, R. B., Zamarin, D., Li, Y., Gasmi, B., Munn, D. H., Allison, J. P., ... Wolchok, J. D. (2015). Tumor-Expressed IDO Recruits and Activates MDSCs in a Treg-Dependent Manner. Cell Reports, 13(2), 412-424. https://doi.org/10.1016/j.celrep.2015.08.077

Tumor-Expressed IDO Recruits and Activates MDSCs in a Treg-Dependent Manner. / Holmgaard, Rikke B.; Zamarin, Dmitriy; Li, Yanyun; Gasmi, Billel; Munn, David H; Allison, James P.; Merghoub, Taha; Wolchok, Jedd D.

In: Cell Reports, Vol. 13, No. 2, 13.10.2015, p. 412-424.

Research output: Contribution to journalArticle

Holmgaard, RB, Zamarin, D, Li, Y, Gasmi, B, Munn, DH, Allison, JP, Merghoub, T & Wolchok, JD 2015, 'Tumor-Expressed IDO Recruits and Activates MDSCs in a Treg-Dependent Manner', Cell Reports, vol. 13, no. 2, pp. 412-424. https://doi.org/10.1016/j.celrep.2015.08.077
Holmgaard, Rikke B. ; Zamarin, Dmitriy ; Li, Yanyun ; Gasmi, Billel ; Munn, David H ; Allison, James P. ; Merghoub, Taha ; Wolchok, Jedd D. / Tumor-Expressed IDO Recruits and Activates MDSCs in a Treg-Dependent Manner. In: Cell Reports. 2015 ; Vol. 13, No. 2. pp. 412-424.
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