Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis

Abstract

Significant progress has been made in cancer immunotherapy with checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)-programmed death-ligand 1 signaling pathways. Tumors from patients showing sustained treatment response predominately demonstrate a T cell-inflamed tumor microenvironment prior to, or early on, treatment. Not all tumors with this phenotype respond, however, and one mediator of immunosuppression in T cell-inflamed tumors is the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) pathway. Multiple mechanisms of immunosuppression may be mediated by this pathway including depletion of tryptophan, direct immunosuppression of Kyn, and activity of Kyn-bound AhR. Indoleamine 2,3-dioxygenase 1 (IDO1), a principle enzyme in Trp catabolism, is the target of small-molecule inhibitors in clinical development in combi-nation with PD-1 checkpoint inhibitors. Despite promising results in early-phase clinical trials in a range of tumor types, a phase III study of the IDO1-selective inhibitor epacadostat in combination with pembrolizumab showed no difference between the epacadostat-treated group versus placebo in patients with metastatic melanoma. This has led to a diminution of interest in IDO1 inhibitors; however, other approaches to inhibit this pathway continue to be considered. Novel Trp-Kyn-AhR pathway inhibitors, such as Kyn-degrading enzymes, direct AhR antagonists, and tryptophan mimetics are advancing in early-stage or preclinical development. Despite uncertainty surrounding IDO1 inhibition, ample preclinical evidence supports continued development of Trp-Kyn-AhR pathway inhibitors to augment immune-checkpoint and other cancer therapies.

Lactate secreted by cervical cancer cells modulates macrophage phenotype

“…Soluble factors secreted by tumor cells, including cytokines, lipid mediators and metabolites can modulate Mϕ phenotype. The later includes adenosine, produced from ATP through the activity of CD39 and CD73 expressed by either tumor or stroma cells, and tryptophan metabolites, as kynurenine, generated through the activity of enzymes as indoleamine‐ 2,3 dioxygenase . Lactate, a by‐product of tumor cell metabolism, secreted to the extracellular environment, exerts an immunomodulatory role in several immune cells .…”

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

“…Increased pro-inflammatory chemokines Immune system modulation (Tokunaga et,al., 2018) 9 Increased Tregs Immune system modulation (Tanaka and,Sakaguchi, 2019) 10 Kyurenine signature Targeted inhibition and immune modulation (Labadie et al, 2019) (Chomienne et al, 1990). If deployed at the appropriate time, treatments that target liabilities of a specific cell state or prevent further adaptation may help improve patient survival by constraining continued tumor evolution towards complete drug resistance.…”

IDO Targeting in Sarcoma: Biological and Clinical Implications

“…Currently, several investigational agents inhibiting the IDO-Kyn-Trp pathway such as IDO1, combination IDO1/TDO inhibitors, AhR inhibitors as well as a recombinant kynureninase are in clinical development or late preclinical testing (18). We investigated the pre-clinical activity of a specific IDO inhibitor-GDC-0919-and its capacity to synergize with PD1 inhibition in a preclinical model of STS.…”