cdc42 Thus far clinical data indicate
Thus far, clinical data indicate that IDO1 inhibitors have manageable toxicity, albeit with a relatively short period of treatment in a small number of patients. KYN is a pluripotent mediator and key intermediate for the synthesis of a host of downstream KP metabolites that are implicated in inflammation, immune modulation, and neurological responses. The eventual KP product is NAD+, a key cofactor required for cdc42 to carry out many biochemical reactions. Therefore, depletion of KYN may alter cellular energy supply as well as immunological and neurological homeostasis . While it is generally accepted that selective inhibition of IDO1 is relatively safe because the liver-resident TDO2 provides basal levels of KYN, it remains to be proven if dual IDO1/TDO2 inhibitors, as well as the KYNase that indiscriminately depletes systemic KYN produced by IDO1/TDO2, could achieve a tolerable therapeutic window in human patients.
The development of cancer immunotherapy in general still lacks biomarkers for patient stratification (see Outstanding Questions). Transitions to precision IO medicine will greatly improve the outcomes of treatment with personalized IO therapeutics as well as reduce failures in clinical trials, and this will require a more detailed understanding of, and the discovery of, new IO therapies specifically targeting the mechanisms underlying tumor immune escape .
Introduction Aryl hydrocarbon receptor (AhR, also named dioxin-receptor) is a proteic ligand-activated transcription factor, expressed in all skin cell types , . It is a central player in skin integrity and skin immunity, responding to exogenous and endogenous chemicals by inducing/repressing the expression of several genes essential for basic skin functions , . The AhR signalling pathway is inducible by small molecules, including environmental toxicants or polycyclic aromatic hydrocarbons, bacterial pigments, or physiological compounds such as tryptophan derivatives or dietary indoles . In the last years, a number of researches have provided that AhR signalling is involved in the pathogenesis of some cutaneous diseases, but its role is contradictory . A variety of studies seem to have demonstrated that blocking AhR activity is suitable to prevent or treat skin cancer, whereas AhR activation could be beneficial in inflammatory skin diseases , , , , . Canonical and non-canonical signalling pathways activated by AhR have been identified (Fig. 1). Canonical AhR signalling is well known , . When inactivate, AhR is commonly found in the cytoplasm in a multiprotein complex with heat shock protein 90 (hsp90), the co-chaperone protein p23 and HBV X-associated protein 2 (XAP-2) , . Various ligands (dioxine, flavonoids, tryptophan photoproducts, Malassezia metabolites) activate AhR that translocates into the nucleus, where AhR nuclear translocator (ARNT) binds to it, releasing hsp90, XAP2 and p23 . The binding of ligand/AhR/ARNT complex to specific DNA recognition site, namely xenobiotic-responsive element (XRE) or dioxin-responsive element genes, induces the transcription of genes encoding both phase I and phase II xenobiotic metabolism enzymes [cytochromes P450 (CYP) 1A1, CYP1A2, CYP1B1 and UDP glucuronosyltransferase 1 family polypeptide A6 (UGT1A6)], associated with adaptive or toxic responses to exogenous agonists , , , , . However, AhR pathway induces a negative feedback arm, via the activity of AhR repressor (AhRR) . The expression of AhRR is regulated by XRE gene and enhanced upon the AhR ligand activation . The AhRR is structurally similar to the AhR and forms a heterodimer with ARNT, inhibiting AhR transcriptional activity . Non-canonical AhR signalling pathways work in a complex manner. Among genes recognized as AhR targets, many do not contain a readily identifiable XRE . Indeed, ligand-AhR-ARNT complex can interact directly with sites distinct from the consensus XRE, such as unliganded estrogen receptor or retinoblastoma protein (RB) , , , . Furthermore, recent studies have identified a novel and specific DNA sequence in the plasminogen activator inhibitor 1 (PAI-1), referred to as non-consensus XRE (NC-XRE), to which AhR binds . The XRE and NC-XRE share no sequence homology, but NC-XRE shares marked homology with the DNA binding sequence of the proteic Kruppel-like factors (KLFs) family . KLFs are a group of transcription factors that appear to be involved in different biological processes . Low activity of transcriptional factor KLF6 has been associated with numerous malignancies suggesting that KLF6 is a tumour suppressor, functioning by regulating expression of the p21Cip1 cyclin-dependent kinase inhibitor , , . Therefore, AhR-KLF6 complex is responsible for normal cell cycle control processes . Indeed, previous studies have demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure can disrupt G1 phase cell cycle progression in cell lines that express a functional AhR, but not in cell lines lacking AhR expression , , , . Another non canonical pathway is mediated by RelB gene, a subunit of the nuclear factor-kappaB (NF-kappaB) . RelB interacts with AhR and binds to an unrecognized genomic RelB/AhR responsive element (RelBAhRE) inducing the production of interleukin (IL)-8, a pro-inflammatory cytokine. This mechanism can be induced by a wide range of stimuli such as tumour necrosis factor (TNF)α, IL-1β, LPS, metals, TCDD, hypoxia, reactive oxygen species, or cellular stress , . Moreover, AhR seems to promote the development of regulatory type 1(Tr1) cells and the transactivation of anti-inflammatory cytokines IL-10 and IL-21 promoters . Under physiological conditions, AhR is constitutively active and canonical and non-canonical-mediated pathways are tightly balanced .