Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive 'Cold' Tumors 'Hot'

Abstract

We discuss how small-molecule inhibitors of the tryptophan (Trp) catabolic enzyme indoleamine 2,3-dioxygenase (IDO) represent a vanguard of new immunometabolic adjuvants to safely enhance the efficacy of cancer immunotherapy, radiotherapy, or 'immunogenic' chemotherapy by leveraging responses to tumor neoantigens. IDO inhibitors re-program inflammatory processes to help clear tumors by blunting tumor neovascularization and restoring immunosurveillance. Studies of regulatory and effector pathways illuminate IDO as an inflammatory modifier. Recent work suggests that coordinate targeting of the Trp catabolic enzymes tryptophan 2,3-dioxygenase (TDO) and IDO2 may also safely broaden efficacy. Understanding IDO inhibitors as adjuvants to turn immunologically 'cold' tumors 'hot' can seed new concepts in how to improve the efficacy of cancer therapy while limiting collateral damage.

Keywords: immunometabolism; immunotherapy.

Figure 1. IDO1 activation is an late-stage event in oncogenesis and immunoediting

Oncogenesis produces cells normally eradicated by immune surveillance due to neoantigen presentation. This process imposes a selection for cells that can escape control. Genetic instability in neoplastically transformed cells facilitates the evolution of escape mechanisms, including a selection for IDO1 dysregulation due to loss of control by the tumor suppressor BIN1, which is often attenuated in cancer cells [144] due to aberrant RNA splicing patterns abolishing its suppressor function [–149] or to altered gene methylation patterns extinguishing its expression [–154]. Resulting skirmishes with tumor cells ‘sculpt’ the immune system to equilibrium, a dynamic yet dormant state of disease, with iteration of escape mechanisms ultimately enabling progressive disease. In the model, genetic alterations initiate tumorigenesis, but the ultimate course to clinically apparent disease is dictated by activation of locoregional modifiers such as IDO1 which influence the host response and act as the etiologic cause of progressive disease with actionable relevance.

Figure 2. Overview of IDO1 regulatory and effector pathways

IDO1 expression is induced at the cellular sites and through the signaling pathways noted, leading to locoregional Trp deprivation plus production of the catabolic product Kyn. IDO1 also has a non-catalytic signaling function that can be stimulated by TGF-ß [19]. Responding cells interpret Trp insufficiency through the mTORC1 and GCN2/eIF-2 pathways, whereas Kyn acts as a native ligand for xenobiotic receptor AHR, with the respective downstream effects on critical pathways for different responding cells shown. IFNs, interferons; ONCs, oncogenic ligand-receptor signaling complexes; PAMP, pathogen-associated molecular pattern (e.g. LPS or CpG ligands for Toll-like receptors [TLR]); DAMP, damage-associated molecular pattern (e.g. extracellular HMGB1 or ATP as ligands for TLR4 or A2A receptors, respectively); B7, T cell co-receptor-ligand complexes (e.g. CD80-CTLA4 or PD1-PDL1) which stimulate ‘reverse signaling’ into APC, including IDO1 induction [29].

Figure 3. Phenotypes of IDO1 and IDO2 nullizygous mice

The figure summarizes evidence that IDO1 requires IDO2 function to induce a PD1-dependent population of Treg cells in mice [12]. It also contrasts phenotypes of Ido1^–/– and Ido2^–/– mice highlighting differences in pathogenic character relevant to cancer and autoimmunity, the latter of which includes desirable and undesirable features that would be separated in an ideal therapeutic response.

Figure 4. 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 Trp deprivation and Kyn 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.

Figure 5. Distinctive mechanistic properties of IDO inhibitors in clinical trials

Tryptophan catabolism proceeds through pathways leading to serotonin or NAD production, the latter through the Kyn pathway which handles ~95% of Trp catabolism in mammals. Epacadostat is >100-fold selective against TDO and displays Trp competitive inhibitory kinetics. Navoximod is ~20-fold selective against TDO and exhibits Trp non-competitive inhibitory kinetics. BMS-986205 is a high-potency suicide inhibitor that irreversibly binds and inactivates IDO1. None of these compounds inhibits IDO2 appreciably. Indoximod is a Trp mimetic which mTORC1 interprets as L-Trp under conditions of high Trp catabolism and autophagy. It also indirectly disrupts IDO2 activity. This compound reverses the disruptive influence of mTORC1 suppression in T cells that results from Trp deprivation generally (i.e. it is a pan-IDO/TDO pathway inhibitor acting downstream on the mTORC effector pathway).

Figure 6. IDO inhibitors as immumometabolic adjuvants to turn ‘cold’ tumors ‘hot’ to immunotherapy, radiotherapy and ‘immunogenic’ chemotherapy

IDO1 inhibitors promote adaptive immunity by relieving immunosuppression of tumor-infiltrating lymphocytes (TILs) including CD8+ T effector cells and natural killer cells. Restraints on the production and anti-neovascular effects of IFNγ mediated by IDO1 are diminished [33, 103]. Further, IDO1 mediation of PD-L1 reverse signals in APC are diminished (Figure 2). In the inflammatory tumor stroma, IDO1 inhibitors block neovascularization, deprive reactive stromal CAF of IDO1 activity, and blunt the production and suppressive activity of MDSC. Preclinical studies show that IDOi potently leverage the efficacy of ‘immunogenic’ radiotherapy and chemotherapeutic drugs, including many DNA damaging drugs [30, 143]. Through these multimodal effects, IDO1 inhibitors act as immunometabolic adjuvants to empower ‘immunogenic’ therapy or frank immunotherapy approaches in otherwise weakly or non-responding tumors as noted.

Figure 7. IDO inhibitors reprogram cancer inflammation and improve therapy

Multiple applications are suggested in various combinations with tolerance blockade (immune checkpoint inhibitors), active immunotherapeutic interventions (vaccines or CART [chimeric antigen receptor T cells]), classical or targeted chemotherapy, and anti-angiogenic therapy or radiotherapy.