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  • br AhR Modulators It is now well

    2023-09-18


    AhR Modulators It is now well recognized that ligand-activated AhR induces an immune tolerance response by acting directly on the antigen-presenting DCs and indirectly by increasing the population of immunosuppressive Tregs 24, 95, 96. In addition to inhibiting the formation or depleting the AhR agonist KYN produced by IDO1/TDO2 enzymes, an alternative strategy to redirect immunity toward tumor rejection is to modulate AhR activation via synthetic antagonists [97]. A challenge unique to the development of selective AhR antagonists is promiscuous ligand binding [98]. Highly structurally diverse compounds, ranging from the heme metabolite biliverdin [99] to dietary product indole-3-carbinol [100], have been described as AhR ligands. Although numerous synthetic and naturally occurring molecules are known to activate AhR signaling [101], only a few tool molecules are available as AhR antagonists and have been used to help to delineate the immunological roles of AhR (Figure 3) 102, 103, 104, 105. The synthetic purine derivative StemRegenin-1 (SR-1) is a selective human AhR antagonist and potently inhibited AhR activation by the high-affinity agonist TCDD (IC50=127nM) [105]. SR-1 has not been evaluated as an IO agent and it is not known if it is capable of inducing anticancer immunity as a single agent or in combination with immune checkpoint inhibitors. It has been applied as an agent to expand hematopoietic stem GSK2656157 in vitro. In a Phase I/II clinical trial, umbilical cord blood (UCB) cells treated with the AhR antagonist SR-1 in cell culture were shown to produce a 330-fold increase in CD34+ hematopoietic stem cells, and led to successful engraftment in all 17 recipients [106]. The development of AhR antagonists as IO therapeutics is still in its infancy. The biotech company Hercules (http://hercules-pharma.nl) is conducting IND-enabling studies of the AhR antagonist HP163 aimed at the treatment of triple-negative breast cancer (TNBC), CRC, and glioblastoma. No biological data for HP163 have been reported. HP163 is likely an optimized derivative of the synthetic flavonoid CB7993113 [104]. CB7993113 competes with TCDD for direct binding to both human and murine AhR, and at 10μM completely blocked agonist-induced AhR nuclear translocation. CB7993113 potently inhibited the migration and invasion of TNBC cells in vitro (IC50=330nM) and antagonized AhR activation in vivo (50mg/kg, i.p.). However, the functional role of AhR in tumorigenesis and cancer metastasis is incompletely understood because ligand-activated AhR was shown to reduce the metastatic ability of breast cancer cells and their stemness 107, 108, 109, 110, 111, 112. It remains to be clarified in clinical settings if an AhR antagonist (or agonist) will elicit antitumor activity by modulating immunity as well as by acting directly on the cancer cells. Persistent activation of AhR in animals and accidental exposure in humans to the environmental toxin TCDD was associated with systemic toxicity, which might be a consequence of the extremely long elimination half-life and high affinity of TCDD. Therefore, pharmacological agents targeting the AhR should be carefully designed to achieve optimal PK/PD profiles and targeted delivery to the desired tissue (i.e., the TME).
    Concluding Remarks and Future Directions In addition to impairing immune effector functions via tryptophan starvation, IDO1 (and TDO2) catalyzes the formation of the endogenous AhR agonist KYN. Ligand-activated AhR promotes the transcription of the immunosuppressive mediators (e.g., IL-10 and PGE2) and the development of regulatory dendritic and T cell populations. Collectively, the available data indicate that cancer cells overexpressing IDO1 and/or TDO2 can evade immune surveillance, and the transcription factor AhR participates in cancer immune escape by binding to the IDO1/TDO2 product KYN. Therefore, therapeutically targeting the IDO1/TDO2–AhR signaling pathway may offer novel anticancer modalities. The first-generation IDO1 inhibitors, exemplified by indoximod and epacadostat, have not demonstrated significant antitumor activity as monotherapy in patients with advanced cancers. Durable responses have been reported for epacadostat combined with the PD-1 immune checkpoint inhibitor pembrolizumab. Surprisingly, objective responses were lacking from a similar combination of navoximod and the PD-L1 antibody atezolizumab. Thus far, the durable clinical activities of IDO1 inhibitors combined with checkpoint inhibitors were more impressive in NSCLC, RCC, SCCHN, and melanoma. Outcomes from ongoing clinical trials of these drug combinations may uncover benefits to patients with breast or prostate cancers. Another confounding factor is the recent description of epacadostat and NLG-919A as AhR agonists with binding affinities at levels similar to KYN [113]. While the implications of this ‘off-target’ activity are unclear, it is reasonable to postulate that it may restrain the immune-activating effect of IDO1 inhibition. The second-generation IDO1 inhibitors, including the best-in-class BMS-986205, are much more potent and are optimized for pharmaceutical properties. These second-generation inhibitors have only recently entered human clinical trials or are under late-stage preclinical evaluation. We anxiously await, with optimism, the clinical results from the IDO1 inhibitor candidates.