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Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer.

ABSTRACT: Many patients with cancer suffer from anemia, depression, and an impaired quality of life (QoL). These patients often also show decreased plasma tryptophan levels and increased kynurenine concentrations in parallel with elevated concentrations of Th1 type immune activation marker neopterin. In the course of anti-tumor immune response, the pro-inflammatory cytokine interferon gamma (IFN-?) induces both, the enzyme indoleamine 2,3-dioxygenase (IDO) to degrade tryptophan and the enzyme GTP-cyclohydrolase I to form neopterin. High neopterin concentrations as well as an increased kynurenine to tryptophan ratio (Kyn/Trp) in the blood of cancer patients are predictive for a worse outcome. Inflammation-mediated tryptophan catabolism along the kynurenine pathway is related to fatigue and anemia as well as to depression and a decreased QoL in patients with solid tumors. In fact, enhanced tryptophan breakdown might greatly contribute to the development of anemia, fatigue, and depression in cancer patients. IDO activation and stimulation of the kynurenine pathway exert immune regulatory mechanisms, which may impair anti-tumor immune responses. In addition, tumor cells can degrade tryptophan to weaken immune responses directed against them. High IDO expression in the tumor tissue is associated with a poor prognosis of patients. The efficiency of IDO-inhibitors to inhibit cancer progression is currently tested in combination with established chemotherapies and with immune checkpoint inhibitors. Inflammation-mediated tryptophan catabolism and its possible influence on the development and persistence of anemia, fatigue, and depression in cancer patients are discussed.

SUBMITTER: Lanser L

PROVIDER: S-EPMC7047328 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer.

Lanser Lukas L Kink Patricia P Egger Eva Maria EM Willenbacher Wolfgang W Fuchs Dietmar D Weiss Guenter G Kurz Katharina K

Frontiers in immunology 20200221

Many patients with cancer suffer from anemia, depression, and an impaired quality of life (QoL). These patients often also show decreased plasma tryptophan levels and increased kynurenine concentrations in parallel with elevated concentrations of Th1 type immune activation marker neopterin. In the course of anti-tumor immune response, the pro-inflammatory cytokine interferon gamma (IFN-γ) induces both, the enzyme indoleamine 2,3-dioxygenase (IDO) to degrade tryptophan and the enzyme GTP-cyclohyd ...[more]

PMID: 32153576

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Project description:BackgroundCancer-related fatigue (CRF) affects a majority of patients (pts) with symptoms lasting up to several years after finishing therapy. These symptoms lead to decreased health related quality of life. Fatigue during treatment for colorectal cancer is common, but poorly understood and can affect compliance with post-surgical cancer therapy. We examined the fatigue levels during first-line chemo- or radio-chemotherapy protocols, which were supported by a pharmaceutical mistletoe preparation (Iscador(®)Qu) (181patients). We compared the outcome to a parallel control group (143 patients), which did not receive this supportive care treatment.MethodsThe medical records of 324 patients with non-metastasized colorectal cancer (UICC stage I-III), which were obtained from hospitals and resident physicians, were assessed. The documented treatment decision by chemo- or radio-chemotherapy supported by mistletoe interventions was followed for a median treatment period of 8.6 months. During the post-surgical treatment period the patients were diagnosed twice for the presence of fatigue symptoms by structural interviews carried out by physicians.ResultsAt the end of the median treatment period, 16/181 patients (8.8%) were diagnosed with CRF in the supportive care group and 86/143 (60.1%) in the chemo- or radio-chemotherapy group without supportive mistletoe medication. Multivariable-adjusted ORs provided evidence for a chance to improve CRF by supportive mistletoe medication compared to chemo- or radio-chemotherapy alone over the time of treatment. The OR = 10.651 (95% CI 5.09-22.28; p < 0.001) declined from the first visit to OR = 0.054 (95 CI 0.02-0.13; p < 0.001) at the end of therapy. Furthermore, 14 confounding factors for risk assessment of CRF were compared by means of forest plots. It turned out that the hospital versus office-based treatment and the co-morbidity/inflammation represent independent but important determinants for fatigue levels.ConclusionThe clinically used mistletoe medication (Iscador(®)Qu) is the first candidate to be included in a supportive care modus into chemo- or chemo-radiotherapy protocols for colorectal patients to improve CRF without discernable toxicities.

Project description:The role of immune or infective triggers in the pathogenesis of Chronic Fatigue Syndrome (CFS) is not yet fully understood. Barriers to obtaining immune measures at baseline (i.e., before the trigger) in CFS and post-infective fatigue model cohorts have prevented the study of pre-existing immune dysfunction and subsequent immune changes in response to the trigger. This study presents interferon-alpha (IFN-α)-induced persistent fatigue as a model of CFS. IFN-α, which is used in the treatment of chronic Hepatitis C Virus (HCV) infection, induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. This model allows for the assessment of patients before and during exposure to the immune trigger, and afterwards when the original trigger is no longer present. Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during the 6-12 months of IFN-α treatment, and at six-months post-treatment. Measures of fatigue, cytokines and kynurenine pathway metabolites were obtained. Fifty-four CFS patients and 57 healthy volunteers completed the same measures at a one-off assessment, which were compared with post-treatment follow-up measures from the HCV patients. Eighteen patients undergoing IFN-α treatment (33%) were subsequently defined as having 'persistent fatigue' (the proposed model for CFS), if their levels of fatigue were higher six-months post-treatment than at baseline; the other 67% were considered 'resolved fatigue'. Patients who went on to develop persistent fatigue experienced a greater increase in fatigue symptoms over the first four weeks of IFN-α, compared with patients who did not (Δ Treatment Week (TW)-0 vs. TW4; PF: 7.1 ± 1.5 vs. RF: 4.0 ± 0.8, p = 0.046). Moreover, there was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-α treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week (TW)4 (p = 0.011 for IL-6 and p = 0.001 for IL-10). There was no evidence of an association between persistent fatigue and peripheral inflammation six-months post-treatment, nor did we observe peripheral inflammation in the CFS cohort. While there were changes in kynurenine metabolites in response to IFN-α, there was no association with persistent fatigue. CFS patients had lower levels of the ratio of kynurenine to tryptophan and 3-hydroxykynurenine than controls. Future studies are needed to elucidate the mechanisms behind the initial exaggerated response of the immune system in those who go on to experience persistent fatigue even if the immune trigger is no longer present, and the change from acute to chronic fatigue in the absence of continued peripheral immune activation.

Dataset Information

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer.

Publications

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer.

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