Tryptophan-degrading enzymes in tumoral immune resistance

Abstract

Tryptophan is required for T lymphocyte effector functions. Its degradation is one of the mechanisms selected by tumors to resist immune destruction. Two enzymes, tryptophan-2,3-dioxygenase and indoleamine 2,3-dioxygenase 1, control tryptophan degradation through the kynurenine pathway. A third protein, indoleamine 2,3-dioxygenase 2, was identified more recently. All three enzymes were reported to be expressed in tumors, and are candidate targets for pharmacological inhibition aimed at restoring effective anti-tumoral immunity. In this review, we compare these three enzymes in terms of structure, activity, regulation, and expression in healthy and cancerous tissues, in order to appreciate their relevance to tumoral immune resistance.

Keywords: adaptive resistance; dendritic cells; immunosuppression; indoleamine 2,3-dioxygenase; tryptophan; tryptophan-2,3-dioxygenase; tumor.

Figure 1

TDO2, IDO1, and IDO2 gene expression in common human normal and tumoral tissues (panels A, B and C, respectively). We used publicly available whole transcriptome data to assess the expression of these three genes in large series of human normal and cancerous tissues. We retrieved raw mRNA counts from the Genome Tissue Expression project (GTEx, see text footnote 1) and The Cancer Genome Atlas (TCGA, see text footnote 2) databases, respectively, normalized the values according to the DESeq approach (23), and represented the results as boxplot graphs for each normal tissue and tumor type, using the R statistical software and the Bioconductor package. The DESeq normalization approach allows to correct the data for the sequencing depth, which affects the number of aligned reads to the gene. It (i) computes the geometric mean for each gene; (ii) divides raw counts for each gene by the corresponding geometric mean; (iii) computes for each sample the median of the obtained ratios; and (iv) divides each gene count by the computed median for the sample. The vertical bars in each box represent, from left to right, the first quartile, median, and third quartile of the indicated sample population. The left and right edge of the horizontal line represents the minimum and maximum values, respectively, after exclusion of the outliers, displayed as individual dots. Several (n = 37) IDO1 outlier values >15,000 have been omitted for the clarity and concision of the graphical display. This approach provides a robust mean to assess the expression of specific genes in the context of malignant diseases, because RNA-Seq data are more precise and have less background than microarray data, and because large series of highly controlled data of various sample types are available from public databases. Carc, carcinoma; H&N, head-and-neck; Paragang, paraganglioma.