IDO1 in cancer: a Gemini of immune checkpoints

Abstract

Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting metabolic enzyme that converts the essential amino acid tryptophan (Trp) into downstream catabolites known as kynurenines. Coincidently, numerous studies have demonstrated that IDO1 is highly expressed in multiple types of human cancer. Preclinical studies have further introduced an interesting paradox: while single-agent treatment with IDO1 enzyme inhibitor has a negligible effect on decreasing the established cancer burden, approaches combining select therapies with IDO1 blockade tend to yield a synergistic benefit against tumor growth and/or animal subject survival. Given the high expression of IDO1 among multiple cancer types along with the lack of monotherapeutic efficacy, these data suggest that there is a more complex mechanism of action than previously appreciated. Similar to the dual faces of the astrological Gemini, we highlight the multiple roles of IDO1 and review its canonical association with IDO1-dependent tryptophan metabolism, as well as documented evidence confirming the dispensability of enzyme activity for its immunosuppressive effects. The gene transcript levels for IDO1 highlight its strong association with T-cell infiltration, but the lack of a universal prognostic significance among all cancer subtypes. Finally, ongoing clinical trials are discussed with consideration of IDO1-targeting strategies that enhance the efficacy of immunotherapy for cancer patients.

Keywords: IDO; Treg; glioblastoma; glioma; immunosuppression; immunotherapy; kynurenine; melanoma.

Figure 1

Tryptophan (Trp) catabolic pathways. In addition to being used as a building block for protein synthesis, the majority of dietary Trp (95%) is catabolized via the Trp→Kyn pathway (red arrows). Other minor pathways include conversion to tryptamine or melatonin. Within the Kyn pathway, the underlined metabolites can cross the blood brain barrier (BBB). IDO1 (and TDO) are highlighted in black boxes. ACMSD: 2-amino-3-carboxymuconate semialdehyde carboxylase; 3-HAO, 3-hydroxyanthranilate 3, 4-dioxygenase; IDO1, indoleamine 2, 3-dioxygenase 1; KAT, kynurenine aminotransferase (I, II, III); KMO, kynurenine 3-monooxygenase; KYNU, kynureninase; MAO, monoamine oxidase; QPRT, quinolinic-acid phosphoribosyl transferase; TDO, tryptophan 2,3-dioxygenase.

Figure 2

The Cancer Genome Atlas analysis reveals distinct correlations between patient survival, IDO1 transcript levels and markers for tumor-infiltrating lymphocytes between glioblastoma (GBM) and melanoma. Top panel: Kaplan–Meier analysis is based on the mRNA expression level of IDO1 in GBM (left column) and melanoma (right column). Expression of IDO1 is divided into low (blue) and high (red) groups as determined by the indicated cutoff value (calculated by Cutoff Finder, Supplementary Table and Methods). The sample size of each group is listed in the parenthesis. Middle panel: canonical correlation analysis (Supplementary Table and Methods) between IDO1 and tumor-infiltrating CD8⁺ T lymphocytes within GBM (left column) and melanoma (right column). Bottom panel: Kaplan–Meier analysis based on the mRNA expression level for the CD8⁺ T cell marker genes CD3E and CD8A in GBM (left column) and melanoma (right column). Expression of CD3E and CD8A are divided into low (blue) and high (red) groups, which were determined by the indicated cutoff value (calculated by Cutoff Finder, Supplementary Table and Methods). The patient sample size for each group is listed in parentheses. *P<0.05; **P<0.01; ****P<0.0001.