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Review
. 2017 Aug;66(8):1049-1058.
doi: 10.1007/s00262-017-2010-2. Epub 2017 May 9.

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

David H Munn  1   2 , Madhav D Sharma  3   4 , Theodore S Johnson  3   4 , Paulo Rodriguez  3
Affiliations
Review

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

David H Munn et al. Cancer Immunol Immunother. 2017 Aug.

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.

Keywords: Chemotherapy; Indoleamine 2,3-dioxygenase; PTEN; Regulatory T cells; Regulatory myeloid suppressor cells; Tolerance.

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Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1
Hypothetical model in which Treg activation is controlled by signals affecting the Akt/mTOR pathway, FoxO3 and a feedback loop between FoxO3, PD–1 and PTEN. The figure is reproduced from Ref. [71] with copyright permission of the publisher
See this image and copyright information in PMC

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