The Kynurenine Pathway Is a Double-Edged Sword in Immune-Privileged Sites and in Cancer: Implications for Immunotherapy

Abstract

The term "immune privilege" was originally coined to describe the suppression of inflammatory responses within organs protected by anatomic barriers, ie, the eyes, brain, placenta, and testes. However, cellular and metabolic processes, which orchestrate immune responses, also control inflammation within these sites. Our current understanding of tolerogenic mechanisms has extended the definition of immune privilege to include hair follicles, the colon, and cancer. By catabolizing tryptophan, cells expressing the enzyme indoleamine-2,3-dioxygenase produce kynurenine metabolites, which orchestrate local and systemic responses to control inflammation, thus maintaining immune privilege. This review highlights the double-edged role played by the kynurenine pathway (KP), which establishes and maintains immune-privileged sites while contributing to cancer immune escape. The identification of the underlying molecular drivers of the KP in immune-privileged sites and in cancer is essential for the development of novel therapies to treat autoimmunity and cancer and to improve transplantation outcomes.

Keywords: HIV; IDO; cancer; immune-privileged sites; kynurenine pathway; tryptophan.

Figure 1

A schematic representation of the key enzymes and metabolites in the kynurenine pathway. Notes: The essential amino acid Trp is consumed via the diet and undergoes catabolism in the digestive tract. Besides its important role in protein synthesis and in serotonin production, Trp is catabolized in various body systems including in the colon by Lactobacilli, and in immune-privileged sites by multiple enzymes, to produce various metabolites. IDO1, IDO2, and TDO are the first rate-limiting enzymes involved in Trp catabolism and produce downstream metabolites collectively referred to as the kynurenines. Since the overproduction of Kyn and its ligation to AhR induce immunosuppressive cells, Kyn is an important therapeutic target. Serotonin, quinolinic acid, and kynurenic acid are Trp metabolites with important roles in normal brain function and in mood disorders. Nicotinamide adenine dinucleotide is an important cellular cofactor produced during Trp catabolism. Abbreviations: AhR, aryl hydrocarbon receptor; GCN2, general control nonderepressible 2; IDO, indoleamine 2,3-dioxygenase; KAT, kynurenine aminotransferase; Teff, effector T cell; Treg, regulatory T cell; TDO, tryptophan 2,3-dioxygenase; Trp, tryptophan.

Figure 2

The role of the kynurenine pathway in inducing tolerance in immune-privileged sites, in tumors, and in the tumor microenvironment. Notes: The production of kynurenine by the IDO enzymatic activity of tumor cells and of APCs leads to immune tolerance in immune-privileged sites and in the tumor microenvironment. Kyn plays a major role by inducing Treg cells, which can also be directly induced by the cytokines and chemokines produced by tumor cells. The cytokines and chemokines produced by tumor cells can also stimulate APCs to activate the KP, which contributes further to tumor development. The four major mechanisms of the KP that influence the immune response are as follows: (1) Trp depletion followed by GCN2 induction and mTOR1 suppression; (2) activation of AhR by Kyn; (3) Treg induction through expression of CTLA-4 and PTEN; and (4) Kyn-mediated blockade of IL-2. Other factors implicated in immune tolerance include tumor cell expression of PD-1/PD-L1 and macrophage expression of MIF. Dotted lines represent decreased Trp concentrations. Abbreviations: AhR, aryl hydrocarbon receptor; APCs, antigen-presenting cells; DC, dendritic cell; GCN2, general control nonderepressible 2; IDO, indoleamine 2,3-dioxygenase; IFN-γ, interferon gamma; IL-32, interleukin-32; KP, kynurenine pathway; Kyn, kynurenine; MDSC, myeloid-derived suppressor cell; MP, macrophage; MIF, macrophage migration inhibitory factor; mTOR1, mammalian target of rapamycin 1; SC, Sertoli cell; Teff, effector T cell; TNF-α, tumor necrosis factor alpha; Treg, regulatory T cell; Trp, tryptophan.

Figure 3

The kynurenine pathway enzyme IDO plays a central role in testicular immune privilege. Notes: IDO expression by Sertoli cells and by macrophages contributes to testicular immune privilege, resulting in tolerance to spermatozoa and to infectious agents. Tissue-resident macrophages express several immunosuppressive molecules, including IDO, arginase-1, IL-10, and TGF-β, which may further induce the production of Treg cells. The BTB plays an important role in the trafficking of immune cells and in the transport of drugs into the testes. The BTB is a physical barrier between the blood or lymph vessels and the lumen of the seminiferous tubules of the testis. Abbreviations: ATP, adenosine triphosphate; BTB, blood–testis barrier; IDO, indoleamine 2,3-dioxygenase; IL-10, interleukin-10; TGF-β, transforming growth factor beta; Treg, regulatory T cell.