Recent studies demonstrated that AHR has an important role

Recent studies demonstrated that AHR has an important role in the interplay between cancer metabolism and tumor-specific immunity. Tryptophan catabolism is increasingly recognized as a metabolic pathway that promotes tumorigenesis through its role in immune suppression [75]. The rate-limiting enzymes tryptophan-2,3-dioxygenase (TDO) and idoleamine-2,3-dioxygenase (IDO), expressed by tumor cells and antigen-presenting cells, are thought to drive the increased catabolism of tryptophan in cancer 30, 76. This metabolic pathway is upregulated in several tumors, including GBM, where it creates an immunosuppressive microenvironment through the depletion of the essential amino Clindamycin Phosphate mg tryptophan and the generation of immunomodulatory tryptophan metabolites, such as Kyn, which suppresses T cell function and induces apoptosis [77]. Importantly, Kyn is an agonist of AHR. Indeed, AHR activation by Kyn promotes Foxp3+ Treg differentiation, supporting earlier reports of a role of AHR in Tregs 9, 78. Of note, AHR also promotes the differentiation of IL-10-producing Tr1 cells 7, 8, which, together with Foxp3+ Tregs, have been shown to contribute to tumor-associated immunosuppression [79]. In addition, AHR has also been linked to Th17 differentiation 79, 80. However, detailed analyses suggest that AHR is more associated with nonpathogenic Th17 cells 80, 81. Indeed, it was shown that AHR drives the expression of the ectoenzyme CD39, which, together with CD73, promotes the production of immunosuppressive adenosine. CD39-expressing Th17 cells with suppressive function have been associated with tumor immunosuppression [82]. AHR also regulates the function of DCs [45], modulating their ability to promote the differentiation of effector and regulatory T cells 11, 13, 83. AHR affects antigen-presenting cell function through several mechanisms. It induces the production of Kyn and retinoic acid (RA) by DCs, boosting the differentiation of Tregs and interfering with effector T cells [84]. AHR also suppresses NF-κB activation in DCs through a mechanism mediated by SOCS2 [85], consequently interfering with the production of cytokines that promote effector T cell differentiation. In addition, AHR controls the activity of resident cells in the central nervous system with inflammatory function, such as astrocytes and microglia [12], which have important roles in the control of the tumor microenvironment. Collectively, these data suggest that Kyn produced by tryptophan metabolism in GBM triggers AHR-dependent effects in multiple components of the immune system to impair tumor-specific immunity. Less is known about the direct role of AHR in the metabolism of cancer cells. Opitz et al. recently reported that TDO in glioma cells produce Kyn, which acts in an autocrine manner to activate AHR and increase tumor growth and invasiveness [30] and can potentially activate AHR on tumor-infiltrating immune cells. Thus, AHR signaling could be elevated in both glioma and inflammatory immune cells in GBM. Taken together, these findings suggest that AHR activation by tryptophan metabolites acts on gliomas and immune cells to promote GBM pathogenesis. Of note, Kyn was proposed as a novel biomarker for meningioma grades because it correlates with cancer pathology, further implicating the role of AHR in brain tumors [86]. Thus, tryptophan metabolites and other tumor-associated AHR ligands may offer useful biomarkers to stratify patients with cancer for immunotherapy.
Crosstalk between AHR and HIF-1α AHR- and HIF-1α-dependent signaling pathways have several points of contact, with important biological consequences. Both AHR and HIF-1α are environmental sensors [87] that dimerize with the same partner (HIF-1β ARNT) to exert their biological effects [45]. Studies using HIF-1β-deficient T cells demonstrated that HIF-1β/ARNT is needed to sustain glycolysis in CD8+ effector T cells [67]. Therefore, this evidence suggests a functional crosstalk between AHR and HIF-1α signaling pathways. Another common binding partner of HIF-1α and AHR, chaperone HSP90, can provide an additional link between two proteins [88].