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Review
. 2014 Oct 6;5:438.
doi: 10.3389/fimmu.2014.00438. eCollection 2014.

Early Carcinogenesis Involves the Establishment of Immune Privilege via Intrinsic and Extrinsic Regulation of Indoleamine 2,3-dioxygenase-1: Translational Implications in Cancer Immunotherapy

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Free PMC article
Review

Early Carcinogenesis Involves the Establishment of Immune Privilege via Intrinsic and Extrinsic Regulation of Indoleamine 2,3-dioxygenase-1: Translational Implications in Cancer Immunotherapy

Alisha Holtzhausen et al. Front Immunol. .
Free PMC article

Abstract

Although prolonged genetic pressure has been conjectured to be necessary for the eventual development of tumor immune evasion mechanisms, recent work is demonstrating that early genetic mutations are capable of moonlighting as both intrinsic and extrinsic modulators of the tumor immune microenvironment. The indoleamine 2,3-dioxygenase-1 (IDO) immunoregulatory enzyme is emerging as a key player in tumor-mediated immune tolerance. While loss of the tumor suppressor, BIN-1, and the over-expression of cyclooxygenase-2 have been implicated in intrinsic regulation of IDO, recent findings have demonstrated the loss of TβRIII and the upregulation of Wnt5a by developing cancers to play a role in the extrinsic control of IDO activity by local dendritic cell populations residing within tumor and tumor-draining lymph node tissues. Together, these genetic changes are capable of modulating paracrine signaling pathways in the early stages of carcinogenesis to establish a site of immune privilege by promoting the differentiation and activation of local regulatory T cells. Additional investigation of these immune evasion pathways promises to provide opportunities for the development of novel strategies to synergistically enhance the efficacy of the evolving class of T cell-targeted "checkpoint" inhibitors.

Keywords: COX-2; Wnt5a; dendritic cells; indoleamine 2,3-dioxygenase; tumor immune evasion; tumor immunotherapy; type III TGF-β receptor; β-catenin.

Figures

Figure 1
Figure 1
Early steps in carcinogenesis include immune evasion by upregulating IDO expression in the tumor microenvironment. This model proposes the development of immune evasion mechanisms early during transformation, which stimulate local IDO activity prior to the development of adaptive anti-tumor immunity and generation of the selective pressure responsible for cancer immunoediting.
Figure 2
Figure 2
Intrinsic and extrinsic mechanisms of IDO regulation in the tumor microenvironment. (A) Downregulation of Bin1 expression leads to enhanced expression of IDO by tumor cells. (B) Upregulation of cyclooxygenase-2 (COX-2) expression by tumor cells stimulates intrinsic tumor expression of IDO. (C) Loss of TβRIII, the gene encoding the type IIII TGF-β receptor (TβRIII), allows for increased TGF-β paracrine signaling in the tumor microenvironment and the upregulation of IDO by local plasmacytoid DCs (pDCs). (D) Increased soluble Wnt5a secretion upregulates IDO expression by local myeloid DCs (mDCs).
Figure 3
Figure 3
Potential pharmacological strategies for suppressing IDO expression in the tumor microenvironment. (A) TGF-β inhibitors. GC1008, pan-TGF-β isoform monoclonal antibody (Genzyme), LY2157299, type I TGF-β receptor serine/threonine kinase small molecule inhibitor (Eli Lilly), TEW-7197, type I TGF-β receptor serine/threonine kinase small molecule inhibitor (MedPacto, Inc.). (B) Wnt inhibitors. LGK974, Porcn acyl transferase small molecule inhibitor (Novartis). (C) Cyclooxygenase-2 (COX2) Inhibitors. Celecoxib (Pfizer, Inc.). pDC, plasmacytoid DC; mDC, myeloid DC.

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