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Blood, 11 June 2009, Vol. 113, No. 24, pp. 6102-6111.
Prepublished online as a Blood First Edition Paper on April 14, 2009; DOI 10.1182/blood-2008-12-195354.
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Submitted December 18, 2008
Accepted April 7, 2009
Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes
Madhav D. Sharma, De-Yan Hou, Yanjun Liu, Pandelakis A. Koni, Richard Metz, Phillip Chandler, Andrew L. Mellor, Yukai He, and David H. Munn*
Department of Pediatrics, Medical College of Georgia, Augusta, GA, United States
Cancer Immunotherapy Program, Cancer Research Center, Medical College of Georgia, Augusta, GA, United States
Department of Medicine, Medical College of Georgia, Augusta, GA, United States
Lankenau Institute for Medical Research, Wynnewood, PA, United States
* Corresponding author; email: dmunn{at}mail.mcg.edu.
The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) is expressed by a subset of murine plasmacytoid DCs (pDCs) in tumor-draining LNs, where it can potently activate Foxp3+ regulatory T cells (Tregs). We now show that IDO functions as a molecular switch in tumor-draining LNs, maintaining Tregs in their normal suppressive phenotype when IDO was active, but allowing inflammation-induced conversion of Tregs to a polyfunctional T-helper phenotype similar to proinflammatory TH17 cells when IDO was blocked. In vitro, conversion of Tregs to the TH17-like phenotype was driven by antigen-activated effector T cells, and required IL-6 produced by activated pDCs. IDO regulated this conversion by dominantly suppressing production of IL-6 in pDCs, in a GCN2-kinase dependent fashion. In vivo, using a model of established B16 melanoma, the combination of an IDO-inhibitor drug plus anti-tumor vaccine caused upregulation of IL-6 in pDCs and in situ conversion of a majority of Tregs to the TH17 phenotype, with marked enhancement of CD8+ T cell activation and anti-tumor efficacy. Thus, Tregs in tumor-draining LNs can be actively re-programmed in situ into T-helper cells, without the need for physical depletion, and IDO serves as a key regulator of this critical conversion.
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