Tobacco carcinogen induces tryptophan metabolism and immune suppression via induction of indoleamine 2,3-dioxygenase 1

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1), the enzyme that catabolizes tryptophan (Trp) metabolism to promote regulatory T cells (Tregs) and suppress CD8+ T cells, is regulated by several intrinsic signaling pathways. Here, we found that tobacco smoke, a major public health concern that kills 8 million people each year worldwide, induced IDO1 in normal and malignant lung epithelial cells in vitro and in vivo. The carcinogen nicotine-derived nitrosaminoketone (NNK) was the tobacco compound that upregulated IDO1 via activation of the transcription factor c-Jun, which has a binding site for the IDO1 promoter. The NNK receptor α7 nicotinic acetylcholine receptor (α7nAChR) was required for NNK-induced c-Jun activation and IDO1 upregulation. In A/J mice, NNK reduced CD8+ T cells and increased Tregs. Clinically, smoker patients with non-small-cell lung cancer (NSCLC) exhibited high IDO1 levels and low Trp/kynurenine (Kyn) ratios. In NSCLC patients, smokers with lower IDO1 responded better to anti-PD1 antibody treatment than those with higher IDO1. These data indicate that tobacco smoke induces IDO1 to catabolize Trp metabolism and immune suppression to promote carcinogenesis, and lower IDO1 might be a potential biomarker for anti-PD1 antibodies in smoker patients, whereas IDO1-high smoker patients might benefit from IDO1 inhibitors in combination with anti-PD1 antibodies.

Tryptophan deficiency induced by indoleamine 2,3‐dioxygenase 1 results in glucose transporter 1‐dependent promotion of aerobic glycolysis in pancreatic cancer

“…Notably, the combination of 1‐MT and BAY876 (combo) exhibited the most potent tumor growth inhibition among the four groups (Figures 6C–E). In addition, 1‐MT significantly suppressed IDO1 activity (reflected by the ratio of Kyn/Trp 44 ) in serum (Figure 6H). Further, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining of tumor tissue sections showed that 1‐MT had a proapoptotic effect while the combo led to a more robust proapoptotic effect than the monotherapy (Figure 6I).…”

Does smoking influence tryptophan metabolism in periodontal inflammation? A cross‐sectional study

“…Our previous study demonstrated that KP is crucial for the etiopathogenesis of periodontal diseases 14 . In the literature, it was shown that smoking has impacts on KP 18,19,39 . Based on this information, in this study, the influence of smoking and periodontal inflammation on salivary and serum TRP‐KYN metabolism was investigated and it was revealed that the KYN/TRP ratio was significantly decreased in saliva in association with periodontitis.…”

“…14 In the literature, it was shown that smoking has impacts on KP. 18,19,39 Based on this information, in this study, the influence of smoking and periodontal inflammation on salivary and serum TRP-KYN metabolism was investigated and it was revealed that the KYN/TRP ratio was significantly decreased in saliva in association with periodontitis. Strikingly, while the salivary KYN/TRP ratio was lowest in the NS-P group, the serum KYN/TRP ratio was the lowest in the S-P group.…”

Effects of dietary intervention on human diseases: molecular mechanisms and therapeutic potential

“… 83 However, within the tumor niche, cancer cells, MDSCs, TAMs, suppressive DCs, and cancer-associated fibroblasts, among other cell types, exhibit upregulated expression of indoleamine 2,3-dioxygenase (IDO), which metabolizes tryptophan into suppressive kynurenine to promote Tregs and suppress CD8 + T cell function. 84 – 86 Most cancer cells overexpress IDO, and the level of kynurenine in the microenvironment is associated with poor prognosis in multiple solid and hematological malignancies. 87 Kynurenine has been found to bind to the aryl hydrocarbon receptor (AHR) in naïve CD4 + T cells, which promotes Treg differentiation.…”