Targeting the IDO1/TDO2–KYN–AhR Pathway for Cancer Immunotherapy – Challenges and Opportunities

IDO1 and TDO2 catalyze the commitment and rate-limiting step of the KYN metabolic pathway that produces the endogenous AhR agonist KYN. Activation of AhR by KYN contributes to the immunosuppressive tumor microenvironment and supports cancer immune escape. Three differential therapeutic modalities, each intercepting a unique node of the IDO1/TDO2–KYN–AhR enzymatic/signaling cascade, have been pursued for the development of novel cancer immunotherapies. Inhibition of IDO1/TDO2 prevents the formation of the endogenous AhR ligand KYN. At least four small-molecule selective IDO1 inhibitors are in clinical development for the treatment of advanced cancers. Systemic depletion of KYN prevents its engagement with AhR. Engineered kynureninase degrades extracellular KYN and shows remarkable efficacy in mouse tumor models. Inhibition of AhR activation by synthetic AhR modulators: an advantage of AhR antagonists is to broadly inhibit the immunosuppressive effect of any endogenous and exogenous AhR ligands. Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) catalyze the commitment step of the kynurenine (KYN) metabolic pathway. Traditionally the immunosuppressive effect of IDO1 has been attributed mainly to reduced levels of tryptophan, which activates the kinase general control nonderepressible 2 (GCN2). Emerging data have shed light on an unexpected role of the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) in transducing the tumor immune escape function imparted by IDO1 and TDO2. AhR activation by the IDO1/TDO2 product KYN leads to the generation of immune-tolerant dendritic cells (DCs) and regulatory T cells, which collectively foster a tumor immunological microenvironment that is defective in recognizing and eradicating cancer cells. Multiple IDO1 inhibitors have been evaluated in clinical trials. There are novel modalities downstream of IDO1/TDO2 for pharmacological interventions. We review recent progress and future perspectives in targeting the IDO1/TDO2–KYN–AhR signaling pathway for the development of novel cancer immunotherapies. Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) catalyze the commitment step of the kynurenine (KYN) metabolic pathway. Traditionally the immunosuppressive effect of IDO1 has been attributed mainly to reduced levels of tryptophan, which activates the kinase general control nonderepressible 2 (GCN2). Emerging data have shed light on an unexpected role of the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) in transducing the tumor immune escape function imparted by IDO1 and TDO2. AhR activation by the IDO1/TDO2 product KYN leads to the generation of immune-tolerant dendritic cells (DCs) and regulatory T cells, which collectively foster a tumor immunological microenvironment that is defective in recognizing and eradicating cancer cells. Multiple IDO1 inhibitors have been evaluated in clinical trials. There are novel modalities downstream of IDO1/TDO2 for pharmacological interventions. We review recent progress and future perspectives in targeting the IDO1/TDO2–KYN–AhR signaling pathway for the development of novel cancer immunotherapies. a member of the basic helix-loop-helix (bHLH)-Per/ARNT/Sim (bHLH-PAS) family of transcription factors. The PAS B domain contains the ligand-binding site that recognizes structurally diverse organic molecules. the occurrence of severe toxicities in human cancer patients that generally involve grade 3 or higher levels of toxicity. They are determined during Phase I clinical trials of cancer therapy. DLTs define the maximum tolerated dose (MTD) that will be applied in later phases of clinical trials. the processes by which cells of the immune system monitor and recognize foreign pathogens or neoantigens in the body. a type II interferon (IFN) cytokine that plays an important role in the regulation of the immune system and the control of infections. IFN-γ produced by cytotoxic T cells contributes significantly to the eradication of cancer cells via adaptive immune antitumor responses. the MTD in human patients is determined during Phase I clinical trials and is the dose used for efficacy studies for the development of anticancer drugs. an in vitro assay to measure T cell reactivity to external stimuli. a heterogeneous group of immune cells of myeloid origin that are potent suppressors of T cell functions. Their population is increased in tumor tissue to support cancer proliferation and metastasis. a type of immunosuppressive T cells that are crucial to modulating immune cell homeostasis to maintain tolerance to self-antigens and to prevent autoimmune disease. Cancer cells upregulate Tregs to induce T cell anergy and evade immunosurveillance. the occurrences of adverse effect related to the use of a drug for treating a disease. TRAEs can be caused by a drug via on-target or off-target actions. the cellular environment that is composed of the cancer cells, immune cells (lymphocytes, MDSCs, dendritic cells, tumor-associated macrophages), fibroblasts, signaling molecules, blood vessels, and the extracellular matrix. The TME is often also characterized by hypoxia (lack of oxygen) and high acidity (lactate from excessive glycolysis) that limit the efficacy of anticancer agents.