Pancancer Analysis of Revealed TDO2 as a Biomarker of Prognosis and Immunotherapy

Abstract

Background. Tryptophan 2,3-dioxygenase (TDO) encoded by TDO2, a rate-limiting enzyme in the kynurenine pathway, catabolizes tryptophan to kynurenine, evades immune surveillance, and promotes tumor growth. Although accumulating evidence suggests a crucial role of TDO2 during tumor formation and development, systematic evaluation of TDO2 across human cancers has rarely been reported. Methods. To shed more light on the role of TDO2 in human cancer, we explored the expression profiles of TDO2 and identified its prognostic value in pancancer analysis through TCGA, CCLE, and GTEx databases. We further utilized TCGA data to evaluate the association between TDO2 and tumor immunological features, such as mismatch repair (MMR), tumor immune infiltration, immune checkpoint-related genes, tumor mutational burden (TMB), microsatellite instability (MSI), and DNA methyltransferase (DNMT). Results. TDO2 exhibited different expression levels in various cancer cell lines. Frequently, TDO2 was detected to be highly expressed in the majority of cancers. In addition, high TDO2 expression was correlated with an unfavorable prognosis for patients in KIRP, LGG, TGCT, and UVM. Moreover, high TDO2 expression level positively correlated with higher immune infiltration, especially dendritic cells. Additionally, there is a close relationship between TDO2 and immune checkpoint-related gene markers, such as LAIR1, CD276, NRP1, CD80, and CD86. Finally, correlation analysis has demonstrated a high-correlation between TDO2 and TMB, MSI, MMR, and DNMT of multiple cancer types. Conclusion. Therefore, our results suggest that TDO2 can function as a potential prognostic biomarker due to its role in tumor immunity regulation.

Identification of therapeutic targets for osteosarcoma by integrating single-cell RNA sequencing and network pharmacology

“…To further screen for differential cell types in OS, the abundance of eight cell types in OS and normal tissues from the GSE36001 dataset was analyzed using the CIBERSORT algorithm (Figure 2A). Studies show that immune checkpoints TDO2, PDCD1, LGALS9, and PVR play an important role in cancer treatment and prognosis (Stamm et al, 2018;Fan et al, 2020;Miao et al, 2020;Cui et al, 2022). Based on Pearson correlation analysis, cell abundance was screened to be significantly correlated with immune checkpoint expression levels, and the results showed that the abundance of B cells, cancer-associated fibroblasts (CAFs), endothelial cells, and plasmocytes were significantly correlated with immune checkpoints TDO2 (p = .043), PDCD1 (p = .017), LGALS9 (p = .017), and PVR (p = .026), respectively (Figure 2B).…”

The kynurenine pathway presents multi-faceted metabolic vulnerabilities in cancer

“…Liver-associated tryptophan 2,3-dioxygenase (TDO2) is another heme-containing enzyme that is involved in the catabolism of Trp to downstream kynurenines ( Figure 1 ) and that has been reported to be frequently overexpressed in various malignancies ( 58 ). Elevated tumoral TDO2 expression is associated with poor prognosis in several cancer types including kidney renal papillary cell carcinoma, glioma, testicular germ cell tumors, and uveal melanoma ( 58 ) as well as liver ( 59 ), colorectal (CRC) ( 60 ), and breast cancer ( 61 ). Moreover, high TDO2 expression level positively correlated with higher immune infiltration, especially DCs, as well as immune checkpoint-related gene markers, such as LAIR1, CD276, NRP1, CD80, and CD86 ( 58 ).…”

“…Elevated tumoral TDO2 expression is associated with poor prognosis in several cancer types including kidney renal papillary cell carcinoma, glioma, testicular germ cell tumors, and uveal melanoma ( 58 ) as well as liver ( 59 ), colorectal (CRC) ( 60 ), and breast cancer ( 61 ). Moreover, high TDO2 expression level positively correlated with higher immune infiltration, especially DCs, as well as immune checkpoint-related gene markers, such as LAIR1, CD276, NRP1, CD80, and CD86 ( 58 ). Regulation of TDO2 expression has been linked to IL-1β- C/EBPβ-MAPK signaling activities ( 62 ).…”