Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer

Abstract

Genetic and pharmacological studies of indoleamine 2,3-dioxygenase (IDO) have established this tryptophan catabolic enzyme as a central driver of malignant development and progression. IDO acts in tumor, stromal and immune cells to support pathogenic inflammatory processes that engender immune tolerance to tumor antigens. The multifaceted effects of IDO activation in cancer include the suppression of T and NK cells, the generation and activation of T regulatory cells and myeloid-derived suppressor cells, and the promotion of tumor angiogenesis. Mechanistic investigations have defined the aryl hydrocarbon receptor, the master metabolic regulator mTORC1 and the stress kinase Gcn2 as key effector signaling elements for IDO, which also exerts a non-catalytic role in TGF-β signaling. Small-molecule inhibitors of IDO exhibit anticancer activity and cooperate with immunotherapy, radiotherapy or chemotherapy to trigger rapid regression of aggressive tumors otherwise resistant to treatment. Notably, the dramatic antitumor activity of certain targeted therapeutics such as imatinib (Gleevec) in gastrointestinal stromal tumors has been traced in part to IDO downregulation. Further, antitumor responses to immune checkpoint inhibitors can be heightened safely by a clinical lead inhibitor of the IDO pathway that relieves IDO-mediated suppression of mTORC1 in T cells. In this personal perspective on IDO as a nodal mediator of pathogenic inflammation and immune escape in cancer, we provide a conceptual foundation for the clinical development of IDO inhibitors as a novel class of immunomodulators with broad application in the treatment of advanced human cancer.

Fig. 1

Sites of IDO expression and action in cancer. IDO expression has been documented in a variety of cells in tumors and tumor-draining lymph nodes (and other metastatic sites) including malignant cells as well as other stromal, vascular and immune cells indicated. Both tryptophan deprivation and kynurenine production mediated by IDO has been implicated in inflammatory processes and the generation of antigenic immune tolerance (immune escape). The figure summarizes the general effects that have been described on T cell function at each site. APC antigen-presenting cell (e.g., dendritic cell), MDSC myeloid-derived suppressor cell, TAM tumor-associated macrophage, TAN tumor-associated neutrophil, Teff T effector cell, Treg T regulatory cell

Fig. 2

IDO programs a pathogenic inflammatory state that supports multiple traits of cancer progression. IDO is highlighted in traits where its role has been functionally implicated in preclinical and clinical studies. The panel below shows the outcome of a regimen of inflammatory skin carcinogenesis in wild-type (WT) and IDO1-deficient (KO) mice, illustrating the essential contributions of IDO function [40]

Fig. 3

IDO regulatory and effector signaling pathways. Multiple upstream-acting regulatory pathways include cell surface receptors which act through intermediary transcription factors (light blue boxes) to stimulate IDO transcription. IDO is also controlled at the level of protein stability by SOCS3 (not shown). Three downstream-acting effector pathways mediate effects of IDO activity (tan boxes), leading to stimulation of AhR by kynurenine binding along with mTOR and eIF-2 suppression due to tryptophan deprivation. Key mediators in each pathway are shown, including IDO2 elevation (via AhR), S6 kinase suppression (via mTOR suppression), and IL-6 and CCL2 elevation (via eiF-2 modulation)

Fig. 4

Strategies for blocking IDO function in cancer. Attenuation of the tumor suppressor Bin1 in malignant cells relieves suppression of IDO transcription through effects on Jak/STAT and NF-kB dependent pathways. IDO upregulation by this mechanism or the stimulatory mechanisms presented in Fig. 3 manifests IDO as a target for cancer therapy, through expression blockade, enzymatic inhibition or effector signal blockade

Fig. 5

Tryptophan deprivation by IDO generates signals sensed by distinct amino acid sufficiency and deficiency pathways. Trp deficiency is sensed by the integrated stress kinase GCN2 that inhibits eIF-2α and alters translation. Through a distinct pathway, the lack of Trp sufficiency causes mTOR to be inactivated, leading to autophagy via LC3 de-repression and translational blockade via S6 kinase inactivation. D-1MT acts as a peculiar mimetic of Trp in the sufficiency pathway, thereby functionally reversing the effects of IDO on mTOR. The figure is modified from Metz et al. [74]

Fig. 6

Immunochemotherapy of the future with IDO inhibitors. Multiple applications are suggested in various combination with tolerance blockade (immune checkpoint inhibitors), active immunotherapeutic interventions (vaccines or CART [chimeric antigen receptor T cells]), and classical/targeted chemotherapy or radiotherapy