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.

Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago

“…At a log2 FC threshold of 0.5 and an FDR of 1%, we are able to recapitulate the main findings of our island-level analyses, although additional trends emerge (Figure 4, Supplementary Figure 7). Detectable differences between villages in the same island are small, with only 71 DMPs and 51 DEGs between the two Mentawai villages of Madobag and Taileleu, and 21 DMPs and 1 DEG, IDO1 (a modulator of T-cell behavior and marker of immune activity 46 ; p = 0.007, log2 FC = −1.48), between the Sumbanese villages of Wunga and Anakalang, echoing their limited separation in the PCA. Similarly, we find low numbers of DEGs and DMPs across all comparisons involving Sumba and Mentawai (Figure 4), again recapitulating the observations we made at the island level (Figure 2).…”

Heterogeneity and targeted therapy-induced adaptations in lung cancer revealed by longitudinal single-cell RNA sequencing

“…We observed a significant (p < 0.0001) increase in the expression of IDO1, KYNU, and QPRT, which are each involved in the kynurenine pathway, in the PD versus TN cancer cells ( Figure 3E, Supplemental Figure 3F, Supplemental Table 2). The kynurenine pathway metabolizes tryptophan generating catabolite intermediates that are further processed to replenish cellular NAD+ and support immunomodulatory roles (Triplett et al, 2018;Zhai et al, 2018). Expression of IDO1, KYNU, and QPRT can result in immunosuppressive behavior (Triplett et al, 2018).…”

Targeting Natural Killer Cells for Tumor Immunotherapy

“…Several proinflammatory cytokines have also been reported to contribute to MDSC-mediated NK cell inhibition, resulting in reduced NK cytotoxicity, decreased expression of activating receptor NKGD or NKR, and limited release of IFN-γ (42). These soluble factors include TGF-β, IDO, nitric oxide (NO), and adenosine (38,(43)(44)(45). Adenosine is an important immunosuppressive molecule that is released at high levels by MDSCs in response to hypoxia and inflammation of the tumor microenvironment.…”