Immunomodulatory Roles of Tryptophan Metabolites in Inflammation and Cancer

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Background

L-Tryptophan (TRP) is one of the essential amino acids in mammals. Beyond its role in protein synthesis, TRP is metabolized along four degradative pathways, leading to the generation of a range of biologically-active metabolites. Three of the pathways are: (i) hydroxylation to serotonin and melatonin; (ii) decarboxylation to tryptamine and (iii) transamination to indolepyruvate. The fourth, which is the kynurenine (KYN) pathway (KP), generates KYN and its downstream metabolites. It is quantitatively the most important degradative, accounting for ~95% of dietary TRP degradation. In addition to endogenous metabolic degradation, the gut microbiota also degrades TRP to bacteria-specific metabolites, such as indole, indolic acid and skatole. Both endogenous and bacteria-derived TRP metabolites exert profound effects on host physiology, including in the immune system.

In the context of inflammation, some KYN metabolites such as 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA) and quinolinic acid (QA) are known to be pro-inflammatory. On the other hand, others such as picolinic acid (PA), kynurenic acid (KA) and xanthurenic acid (XA) are known to have anti-inflammatory functions. An accumulating number of recent studies have revealed an immensely important link between TRP metabolism, inflammation and the regulation of immune responses. In particular, TRP metabolites have been shown to modulate the functions of various T cell subsets by acting through pro-inflammatory cytokines, such as IFN-γ , IL-2 or TNF-α in Th1 cells, and by acting through anti-inflammatory cytokines such as IL-4 or IL-10 in Th2 cells. These processes consequently impact on immune-modulation in various inflammatory disorders, including inflammatory bowel disease and neuroinflammatory diseases.

In the context of cancer, various types of tumors are known to exploit the ability of pro-inflammatory TRP metabolites to undermine the ability of effector immune cells mount anti-tumor responses, leading to tumoral immune escape. One mechanism by which tumors achieve this escape is by enhancing their own uptake of TRP by upregulating the expression of amino acid transporters and TRP degradation by expressing indoleamine 2,3-dioxygenase and/or TRP 2,3-dioxygenase. The increased generation of TRP metabolites, in turn, induces the arrest of invading T cells, promoting the development of an immunosuppressive tumor microenvironment.

Given the immuno-modulatory roles of TRP metabolites in inflammation and cancer, these molecules are now being considered as promising novel biomarkers of disease. In addition, their biosynthetic routes have been rendered as attractive targets for immunotherapeutic interventions.

In this Research Topic, we aim to illustrate the current state of research on the immunomodulatory properties of TRP metabolites and their roles in inflammation and cancer. We also aim to provide a stimulus for developmental efforts towards the application of TRP metabolites in immunotherapy. We welcome the submission of Original Research Articles, Reviews and Mini-Reviews covering, but not limited to, the following:

A. TRP metabolism and its modulation by inflammatory mediators

1. Pathways of TRP metabolism in immune cells, and in non-immune cells with immuno-modulatory properties.
2. Quinolinate: a marker of TRP metabolite formation and the unresolved question of NAD+ synthesis during infection and inflammation.
3. Effects of acute and chronic inflammation on TRP metabolism.

B. Immunomodulatory effects of TRP metabolites in health and disease

1. Regulation of antibody responses by TRP metabolites.
2. Immunomodulation of neuroinflammation by pro-inflammatory TRP metabolites.
3. Interplay between TRP metabolites and T cell regulation.
4. Interaction of TRP metabolites with immune-associated receptors during inflammation.
5. The immune-pineal axis: role of melatonin in integrating the circadian clock and immune responses.
6. TRP metabolites in immuno-suppressive microenvironments.

C. Targeting TRP metabolism for immuno-therapeutic intervention

1. TRP availability in tumoral immune escape.
2. Role of TRP metabolites in immunotherapy of cancer.
3. Pro-inflammatory TRP metabolites for immunotherapy of neuroinflammatory and neurodegenerative diseases.
4. Immunotherapy of inflammatory bowel diseases and irritable bowel syndrome.
5. Targeting TRP metabolites for treatment of inflammation during infection.
6. Immunotherapy of acute inflammation of septic shock using 1-methyltryptophan.
7. Side effects of immunotherapeutic intervention using TRP analogues.

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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