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Dynamic change of IDO1 activity predicts survival in patients with unresectable stage III NSCLC and chemoradiotherapy

ABSTRACT:

OBJECTIVES: High activity of Indoleamine 2,3-dioxygenase1 (IDO1) in lung cancer patients converts tryptophan (Trp), which is the essential amino acid for T cell metabolism, to kynurenine (Kyn) and consequently suppresses anti-tumor immune responses. We aimed to track the dynamics of IDO1 activity in stage III non-small cell lung cancer (NSCLC) patients who received first-line radiotherapy (RT) and explore its association with survival outcomes.

MATERIALS AND METHODS: Systemic IDO1 activity was calculated by Kyn:Trp ratio. Plasma levels of Kyn and Trp in 113 thoracic RT-received stage III NSCLC patients were measured by high-performance liquid chromatography before the initiation of RT. Dynamic change of IDO1 activity was followed in 24 patients by measuring Kyn:Trp ratio before, during and after RT administration.

RESULTS: In 24 patients with dynamic tracking of plasma IDO1 activity, there was no significant alterations observed among the 3 time points (Friedman test, p=0.13). The changing pattern of Kyn:Trp ratio was divided into 4 groups: decreased consistently during RT, first increased then decreased, increased consistently, first decreased then increased. Patients whose Kyn:Trp ratio kept decreasing or first increased then decreased were defined as good-change group. The good-change status was identified as an independent positive factor for overall survival (OS) and progression-free survival (PFS) (p=0.04; p=0.01) in multivariate analysis among evaluated parameters. Patients with good change showed significantly superior local control than bad-change group (p=0.01, HR=0.22). In 113 stage III NSCLC patients with pre-radiation Kyn:Trp ratio, a trend that high baseline IDO1 activity was associated with short OS was observed (p=0.079).

CONCLUSION: Favorable change of IDO1 activity during RT was associated with superior OS, PFS and local control. IDO1 activity is a promising biomarker for prognosis in stage III NSCLC patients.

INSTRUMENT(S): Liquid Chromatography MS -

SUBMITTER: Qian Minmin

PROVIDER: MTBLS5267 | MetaboLights | 2022-08-05

REPOSITORIES: MetaboLights

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Project description:In 2020, lung cancer remains the most diagnosed entity among men and third most among women, causing approximately 1.8 million deaths worldwide with an estimated 31.5% of new cases in men and 14.6% in women, respectively (1). Moreover, metastasized non-small cell lung cancer (NSCLC) continues to be one of the cancer entities with the worst prognosis as well as disease-free and overall survival despite the recent introduction of immunotherapy, with the patients’ 5-year-survival rate ranging still only between 10-20% (1). The development of cancer and metastasis is considered a multi-step process in which many factors are the topic of ongoing investigation. Thus, the identification of novel markers and targets, which are involved in disease progression, is an essential step in improving the survival of lung cancer patients. Previously, we identified HECT and RLD domain containing E3 ubiquitin protein ligase 5 (HERC5) gene as the main target gene on 4q (6). Loss of 4q has been associated with advanced disease stage and worse prognosis in several cancer entities including lung, colorectal, pancreatic, and hepatocellular cancer (2–5). We showed that in NSCLC, HERC5 downregulation via promoter hypermethylation leads to an increase in disseminated tumor cells (DTCs) and occurrence of brain metastases in NSCLC as well as poorer overall survival (OS) (6). In hepatocellular cancer, low mRNA expression levels of HERC5 could similarly be correlated with shorter OS, which led to immune evasion by indirectly increasing infiltration by regulatory T-cells (5). It was thus postulated that HERC5 might serve as a novel metastasis suppressor gene. Originally described in the context of innate immune responses, HERC5 is known to serve as the cellular main E3 ligase of ubiquitin-like modifier interferon-stimulated gene 15 (ISG15) (7,8), thereby catalyzing the transfer of ISG15 onto target proteins – a process called ISGylation. ISGylation is not only an important primary defense mechanism against viruses and other pathogens (9,10), but also associated with various diseases such as immunodeficiencies, neurodegenerative disorders and different types of cancer (11–14). Lately, energy metabolism has been proven to have a strong influence on tumorigenesis and metastasization (15–17). Given the enhanced energy demand of highly proliferating cells, tumor cells can undergo a change in energy consumption mechanisms – such as the well-described Warburg-effect, leading to a switch between ATP production through glycolysis rather than oxidative phosphorylation (OXPHOS) (18). Despite the lower yield in ATP through glycolysis, malignant cells often prefer this pathway even in the presence of oxygen, leading to an increase in metabolic byproducts which are necessary for the elevated demand of metabolites required due to their high proliferation rates (15,16). Deregulation of ISG15 have been linked to dysfunctional mitochondria as well as altered OXPHOS activity (19–22). In this study, we aimed at further elucidating the potential metastasis suppressing role of HERC5 in NSCLC. We therefore assessed the malignant potential of HERC5 loss in in vitro and in vivo NSCLC models and could confirm its capacity to transform NSCLC cells both in vitro and in vivo into a more aggressive phenotype. We furthermore performed mass spectrometry analyses to identify the main pathways altered by differential HERC5 expression in modified NSCLC cell lines and could show that HERC5 has an influence on mitochondrial composition, and energy metabolism pathways such as OXPHOS, leading to better adaptation and survival under prolonged inhibition of oxidative phosphorylation.

			Action	DRS
	MTBLS5267	Other
	FILES	Other
	a_MTBLS5267_LC-MS___metabolite_profiling.txt	Txt
	files-all.json	Other
	i_Investigation.txt	Txt

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Dynamic change of IDO1 activity predicts survival in patients with unresectable stage III NSCLC and chemoradiotherapy

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