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IDO, PTEN-expressing Tregs and control of antigen-presentation in the murine tumor microenvironment

  • Focussed Research Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

The tumor microenvironment is profoundly immunosuppressive. This creates a major barrier for attempts to combine immunotherapy with conventional chemotherapy or radiation, because the tumor antigens released by these cytotoxic agents are not cross-presented in an immunogenic fashion. In this Focused Research Review, we focus on mouse preclinical studies exploring the role of immunosuppressive Tregs expressing the PTEN lipid phosphatase, and the links between PTEN+ Tregs and the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). IDO has received attention because it can be expressed by a variety of human tumor types in vivo, but IDO can also be induced in host immune cells of both humans and mice in response to inflammation, infection or dying (apoptotic) cells. Mechanistically, IDO and PTEN+ Tregs are closely connected, with IDO causing activation of the PTEN pathway in Tregs. Genetic ablation or pharmacologic inhibition of PTEN in mouse Tregs destabilizes their suppressive phenotype, and this prevents transplantable and autochthonous tumors from creating their normal immunosuppressive microenvironment. Genetic ablation of either IDO or PTEN+ Tregs in mice results in a fundamental defect in the ability to maintain tolerance to antigens associated with apoptotic cells, including dying tumor cells. Consistent with this, pharmacologic inhibitors of either pathway show synergy when combined with cytotoxic agents such as chemotherapy or radiation. Thus, we propose that IDO and PTEN+ Tregs represent closely linked checkpoints that can influence the choice between immune activation versus tolerance to dying tumor cells.

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Abbreviations

CCR4:

C-C chemokine receptor type 4

FoxO3:

Forkhead box O3

GCN2:

General control nonderepressible-2

KO:

Knockout

mTOR:

Mechanistic target of rapamycin

mTORC:

mTOR kinase complex

PTEN:

Phosphatase and tensin homolog

Tregs:

Regulatory T cells

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Acknowledgements

Supported in part by Grants CA096651 and CA103320 from the National Institutes of Health, and the Beloco foundation.

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Authors and Affiliations

  1. Georgia Cancer Center, Medical College of Georgia, Augusta University, Room CN4141, Augusta, GA, 30912, USA

    David H. Munn, Madhav D. Sharma, Theodore S. Johnson & Paulo Rodriguez

  2. Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA

    David H. Munn, Madhav D. Sharma & Theodore S. Johnson

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  1. David H. Munn
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  2. Madhav D. Sharma
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Correspondence to David H. Munn.

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Conflict of interest

David Munn is a consultant to NewLink Genetics Corporation and holds intellectual property in IDO-inhibitors and PTEN-inhibitors. Theodore Johnson receives funding for clinical trials of IDO-inhibitors from NewLink Genetics, Inc. The authors declare that there are no other conflicts of interest.

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This paper is a Focussed Research Review based on a presentation given at the conference Regulatory Myeloid Suppressor Cells: From Basic Discovery to Therapeutic Application which was hosted by the Wistar Institute in Philadelphia, PA, USA, 16th–19th June, 2016. It is part of a Cancer Immunology, Immunotherapy series of Focussed Research Reviews.

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Munn, D.H., Sharma, M.D., Johnson, T.S. et al. IDO, PTEN-expressing Tregs and control of antigen-presentation in the murine tumor microenvironment. Cancer Immunol Immunother 66, 1049–1058 (2017). https://doi.org/10.1007/s00262-017-2010-2

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