Tumours increase their consumption of the amino acid tryptophan to evade immune control. But how does this work? A study shows that the main product of this consumption binds to a receptor involved in the immune system. See Article p.197
There is mounting evidence that fast-growing 'progressive' cancers occur because of a failure of the immune system to maintain control over budding tumours. The ability of cancers to escape immune responses is therefore attracting increasing attention, with numerous studies now pointing, perhaps surprisingly, to the consumption of the amino acid tryptophan as a critical factor in progressive cancer. On page 197 of this issue, Opitz et al.1 advance the field with their finding that many cancers upregulate a liver enzyme, tryptophan dioxygenase, to drive tryptophan consumption. What's more, the authors find that the primary product of this process, kynurenine, is an endogenous ligand for the aryl hydrocarbon receptor, which mediates invasive tumour growth. This second finding links the fields of toxicology, immunology and cancer biology in new ways, and may help to explain how elevated tryptophan consumption helps tumours to overcome immune barriers to cancer progression.
Cancer has its roots in altered gene structure and expression, but the tissue microenvironment in which a cancer arises poses a huge barrier to its development and progression. In particular, the complex interplay between cancer cells and nearby immune cells may be one of the most important determinants of whether an early cancer is destroyed by the immune system, persists in a dormant or slow-growing state (such tumours are often localized and treatable), or progresses to a clinically challenging invasive or metastatic state.
Immune escape represents a budding tumour's victory in its constant thrust and parry with the immune system, which detects accumulating genetic damage in cancer cells. This battle, which is coordinated with oncogenic processes, selects for cancer cells that can resist immune detection or eradication. Immune escape therefore drives the development of tumours towards increasingly aggressive forms2. Intriguingly, many pathways of immune escape involve active suppression of the immune system by tumour cells, implying that disruption of these suppressive pathways could restore immune attack. One such pathway that is of emerging importance in cancer involves the consumption of tryptophan and generation of kynurenine by the indoleamine 2,3-dioxygenase enzymes IDO and IDO2, and also by tryptophan dioxygenase (TDO), as Opitz et al.1 report.
The fundamental role of IDO in immune tolerance was recognized several years before its connections to cancer, and it is by far the most broadly expressed and studied of the tryptophan-metabolizing enzymes3,4. IDO's action leads to tryptophan depletion and kynurenine generation, which cooperate to inhibit the activation of immune cells known as T cells through various mechanisms that also affect the activities of other classes of immune cells5,6. In addition to cancer cells themselves, dendritic cells and regulatory B cells of the immune system may be key sites of IDO action for initiating and maintaining antigenic tolerance, the process that prevents the immune system from recognizing and attacking tumours. IDO has also been implicated in chronic viral infections and allergies, and in various autoimmune and inflammatory disorders in which immune control is disrupted7.
In patients with cancer, the upregulation of IDO is often associated with a poor prognosis8. Genetic ablation of the enzyme in mice has confirmed that IDO has crucial roles in immune tolerance and inflammatory carcinogenesis (tumour growth associated with chronic inflammation), with IDO expression in tumour cells, immune cells and stromal cells apparently contributing to its functions in cancer-associated inflammation, immune escape and tumour outgrowth9,10. Pharmacological studies have shown that IDO inhibitors are efficacious anticancer agents, especially when used as adjuvants to improve the efficacy of immunochemotherapy, radiotherapy and cancer vaccines11. Indeed, clinical trials of IDO inhibitors as adjuvant anticancer agents are now under way. What's more, the powerful efficacy of the anticancer drug imatinib in the treatment of solid gastrointestinal stromal tumours may be a result of IDO inhibition by the drug12.
Opitz et al.1 reveal that, like IDO, TDO is frequently activated in cancer, particularly in cases in which IDO is not activated. This is the situation in a type of brain cancer called glioma, for example, in which the authors performed their studies. Their work is the first to connect TDO to cancer biology. One unique aspect of TDO is that its activation promotes cancer-cell migration, something that IDO has not been reported to do. This suggests some divergence in function between the two enzymes, despite their shared ability to generate kynurenine. TDO is structurally dissimilar to IDO and IDO2, but all three enzymes can consume substrates other than tryptophan. If TDO's substrate preference differs from that of the IDO enzymes, this might differentiate its biological functions from those of IDO or IDO2 to some extent. Whatever the case, Opitz and colleagues' work suggests that TDO inhibitors might be important for cancer studies, both because they may be useful in treating IDO-independent cancers and because TDO activation could be one way for tumours to acquire resistance to IDO inhibitors.
Notably, Opitz et al. also report that kynurenine is an endogenous ligand of the aryl hydrocarbon receptor (AHR) that mediates a signalling pathway from TDO (or IDO) to AHR in driving malignant growth (Fig. 1). AHR is a xenobiotic receptor — one that responds to foreign substances in the body — and is most widely known to bind to 2,3,7,8-tetrachlorodibenzo-p-dioxin, a potent toxic chemical that powerfully suppresses antibody and cellular immune responses, stimulates carcinogenesis and promotes tumour outgrowth. Previous work has suggested that kynurenine can bind to AHR to promote the generation of immune-suppressive T cells that support cancer development13. The binding of kynurenine to AHR causes the receptor to move into the nucleus, where it binds target genes and activates their transcription, leading to tumour migration. Genetic studies in mice have defined roles for AHR in immune regulation, inflammation and carcinogenesis14, the same processes in which IDO has been implicated15.
Opitz et al.1 found that elevated levels of AHR in tumours corresponded with a poor prognosis in patients, supporting a similar connection between TDO overexpression and patient outcome. Their discovery of kynurenine as an endogenous ligand for AHR in cancer helps to explain why tumours select for IDO- or TDO-mediated tryptophan consumption: the kynurenine that is produced binds to AHR and helps tumours to achieve immune escape. The connection between tryptophan consumption and AHR activation may also explain why inflammation and immune escape supported by tryptophan consumption are so integrally connected in cancer15. Intriguingly, although IDO2 is still little understood, the gene encoding it is one of those regulated in dendritic cells by AHR activation16. Along with other evidence17, this connection hints at a feedback loop between AHR and tryptophan consumption, suggesting that the IDO/TDO–kynurenine–AHR signalling pathway might dynamically modulate inflammation and immunity.
Given that AHR is likely to be a widespread mediator of kynurenine responses, AHR studies from the field of toxicology could have a large conceptual impact on tumour immunology and cancer biology. Opitz and colleagues' work1 also begs many questions. Does kynurenine act as a general migratory signal for immune cells or cancer cells? Might AHR effector signals distinguish between the functions of IDO and TDO in inflammation and immune tolerance? And could existing AHR activators or blockers be used to treat diseases that involve IDO, TDO and kynurenine? These issues provide a basis for exciting research opportunities in the future.
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