IDO1: An important immunotherapy target in cancer treatment

doi:10.1016/j.intimp.2017.03.024

International Immunopharmacology

Volume 47, June 2017, Pages 70-77

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Concentrating on molecular mechanism of IDO1 in immune toleration and complex environments of cancer, IDO1 inhibitor could cooperate with chemotherapies and other immune targets to lessen the tumor as possible.

Abstract

Indoleamine 2,3-dioxigenase 1 (IDO1) acts in pathogenic inflammatory processes and engender immune tolerance to tumor antigens. IDO1 can decrease the tryptophan and produce a series of toxic kynurenine metabolites to promote the immune toleration via GCN2 pathway, mTOR pathway, toxic effect of kynurenine and favoring differentiation of Tregs. IDO1 can be induced in most human cells, especially APCs and cancer cells through canonical and non-canonical NF-κB and Jak/STAT pathways, as well as PKC and TGF-β signaling pathways. A series of human cancers over-express IDO1 in a constitutive way. Thus, IDO1 is likely to be an attractive target for developing inhibitors of tumor treatments. Many preclinical and clinical trials have been underway and suggest that IDO1 inhibitor maybe an effective tool against a wide range of cancers. However, the IDO1 inhibitor alone had been verified that to be disappointment in achieving effective antitumor efficacy. Concentrating on its molecular mechanism in immune toleration and complex environments of cancer, IDO1 inhibitor could cooperate with chemotherapies and other immune target inhibitors to lessen the tumor.

Introduction

Tryptophan (Trp) is used in a variety of catabolic processes and metabolized into serotonin, melatonin, niacin, auxins, and kynurenine (Kyn). The first, rate-limiting step of the Kyn pathway of Trp metabolism can be catabolized by three different enzymes, including indoleamine 2,3-dioxigenase 1 (IDO1), IDO2, and Tryptophan 2,3-dioxigenase (TDO2) [1], [2], [3]. IDO1 (EC1.13.11.52), which is encoded by the IDO1 gene, is by far the best characterized, which was involved in the host response to microbial challenges as early as in the late 1970s [4]. The human IDO1 gene was located on the p arm of chromosome 8 at position 11.21 and contain 10 exons. IDO1 is inducing Trp metabolize, as a result, to cause suppressing growth of cells, especially immune cells. Trp metabolism has been identified as a metabolic checkpoint of immuno-regulation [2], [5].

Section snippets

The biology effect of IDO1

Cells that express IDO1 create two effects in microenvironments around them: decreasing Trp and producing a series of toxic Kyn metabolites [5], [6], [7], shown in Fig. 1.

The former effect can resulting in activation of the amino acid-sensitive general control non-depressible 2 (GCN2) stress kinase pathway [8], [9] and mammalian target of rapamycin (mTOR) pathway [10], the GCN2 activation can elevates interleukin-6 (IL-6) and CC chemokine ligand 2 (CCL2) [8]. As a result, it leads to cell cycle

IDO1 and cancer

Many previous studies have verified that IDO1 is silent in most tissues. Accelerated Trp break down via IDO1 has been reported to occur in several disorders such as neuro degeneration [28], cardiovascular disease [29], infections [30] and malignancies [31], [32]. Focus on malignancies, IDO1 acts in tumor, stromal and immune cells to encourage pathogenic inflammatory processes which breed immune tolerance to tumor antigens. Immune cells are often present at the tumor site, not only to recognize

IDO1 inhibitor and cancer treatment

The interactions among inflammation, IDO1, and cancer are noteworthy and raise critical questions regarding how and when to optimally target Trp catabolism for therapeutic purpose. Based on its key role in immuno-suppression and cancer, IDO1 is likely to be an attractive target for the development of inhibitors for tumor treatments [1], [36], [56]. It was hypothesized that an inhibitor of IDO1 would increase the effectiveness of the T-cell in tumor microenvironments.

Several preclinical studies

Indoximod

The first-in-man Phase I clinical trial, NCT00567931, was started in Dec, 2007 to investigate safety, toxicity and maximally biological effective dose of indoximod for 48 refractory solid malignancies [58]. Patients are treated with up to 6 consecutive 28-day cycles starting at 200 mg once daily. Ten patients have received indoximod at 200 mg daily. Of the 7 evaluable patients, 4 had stable disease and 3 had progressive disease. Attributable toxicities were 1 case of grade 1 fatigue and 2 cases

IDO1 inhibitor and chemotherapy

As mentioned above, targeting IDO1 as a standalone therapeutic agent often fails to cause tumor regression. Thus, IDO1 inhibitors have been evaluated for their ability to improve the efficacy of multiple chemotherapeutics, and some combinatorial regimens of this type had promising results in preclinical studies [44], [60]. From a clinical standpoint, combining IDO1 inhibitors with conventional chemotherapy drugs represents an attractive scheme, and a mechanistic rationale supporting such

IDO1 inhibitor and immunotherapy treatment

Immunotherapy is a promising strategy for cancer therapy. Therapeutic vaccination of cancer patients is an approach to stimulate their immune system against cancer cells. This therapy, however, showed limited efficacy in vivo. Cancer cells are actually able to develop enzymatic mechanisms allowing tumors to resist or escape immune rejection.

Because IDO1 inhibition might increase the effectiveness of immunotherapies in patients with cancer on the basis of the reported effects and mechanism of

IDO1-derived peptide

It has recently exhibited the results of a Phase I clinical trial evaluating the safety and therapeutic profile of an IDO1-targeting, peptide-based vaccine (NCT01219348). In this setting, Fifteen HLA-A2-positive individuals with metastatic NSCLC experienced disease stabilization under standard chemotherapy received an IDO1 derived peptide survivac in combination with the TLR7 agonist imiquimod [73]. One patient achieved a partial response one year after vaccination, and 6 patients had longer (>

Conclusion

Continue higher IDO1 expression in the tumor microenvironment has been evidenced play important role in cancer progression and metastasis. However, the IDO1 inhibitor alone had be verified to be disappointment in effective antitumor efficacy. Concentrating on its molecular mechanism in immune toleration and complex immune microenvironments of cancer, IDO1 inhibitor could cooperate with other chemotherapies and immune targets to lessen the tumor as possible via multi-path therapies.

Competing interests

The authors declare that they have no competing interests.

Funding

The work was supported partially by National Natural Science Fund of China (81502309).

Authors' contributions

Fangxuan Li: study design and manuscript write.

Rupeng Zhang: study design and manuscript review.

Shixia Li: reference prepare and manuscript write.

Juntian Liu: reference prepare and manuscript review.

Acknowledgement

None.

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ReviewIDO1: An important immunotherapy target in cancer treatment

Highlight

Abstract

Introduction

Section snippets

The biology effect of IDO1

IDO1 and cancer

IDO1 inhibitor and cancer treatment

Indoximod

IDO1 inhibitor and chemotherapy

IDO1 inhibitor and immunotherapy treatment

IDO1-derived peptide

Conclusion

Competing interests

Funding

Authors' contributions

Acknowledgement

Biochem. Biophys. Res. Commun.

Immunity

Immunol. Lett.

Blood Cells Mol. Dis.

Horm. Behav.

Immunol. Lett.

Am. J. Pathol.

Int. Immunopharmacol.

Gynecol. Oncol.

J. Am. Coll. Surg.

Gynecol. Oncol.

Semin. Oncol.

Value Health

IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism [J]

Cancer Immunol. Immunother.

Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for the trees? [J]

Nat. Rev. Cancer

Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites [J]

Proc. Natl. Acad. Sci. U. S. A.

Exploring the mechanism of tryptophan 2,3-dioxygenase [J]

Biochem. Soc. Trans.

Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase [J]

Nat. Med.

T cell apoptosis by kynurenines [J]

Adv. Exp. Med. Biol.

IDO-GCN2 and autophagy in inflammation [J]

Oncotarget

IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: a novel IDO effector pathway targeted by D-1-methyl-tryptophan [J]

Oncoimmunology

Reduced cytotoxic function of effector CD8 + T cells is responsible for indoleamine 2,3-dioxygenase-dependent immune suppression [J]

J. Immunol.

Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase [J]

J. Exp. Med.

Indoleamine-2,3-dioxygenase, an immunosuppressive enzyme that inhibits natural killer cell function, as a useful target for ovarian cancer therapy [J]

Int. J. Oncol.

An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells [J]

J. Immunol.

Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease [J]

Sci Transl Med

Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3(+) regulatory T cells [J]

Nat. Immunol.

Distinct tryptophan catabolism and Th17/Treg balance in HIV progressors and elite controllers [J]

PLoS One

Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase [J]

J. Clin. Invest.

CD28 induces immunostimulatory signals in dendritic cells via CD80 and CD86 [J]

Nat. Immunol.

Transcription factor Foxo3 controls the magnitude of T cell immune responses by modulating the function of dendritic cells [J]

Nat. Immunol.

Innate and adaptive immune cells in the tumor microenvironment [J]

Nat. Immunol.

Cutting edge: induced indoleamine 2,3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion [J]

J. Immunol.

Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes [J]

J. Clin. Invest.

The tryptophan catabolite l-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function [J]

Blood

T and NK cells: two sides of tumor immunoevasion [J]

J. Transl. Med.

Review
IDO1: An important immunotherapy target in cancer treatment