Imaging correlates of differential expression of indoleamine 2,3-dioxygenase in human brain tumors

Abstract

Background: Tryptophan catabolism via the kynurenine pathway, mediated by indoleamine 2,3-dioxygenase (IDO), is a mechanism involved in tumor immunoresistance. Positron emission tomography (PET) with alpha-[(11)C]methyl-L-tryptophan (AMT) can quantify transport and metabolism of tryptophan in infiltrating gliomas and glioneuronal tumors. In the present study, we investigated whether increased tryptophan metabolism in brain tumors measured by PET is related to expression of IDO in resected brain tumor specimens.

Methods: IDO expression was assessed by immunohistochemistry in tumor specimens from 15 patients (median age, 34 years) with primary brain tumors who underwent AMT PET scanning before tumor resection. Patterns of IDO expression were compared between low- and high-grade tumors and also to AMT transport and metabolism measured on PET.

Results: IDO immunoreactivity was seen in tumor cells in six of seven low-grade tumors but only in one of eight high-grade tumors (p = 0.01); three of these latter tumors showed endothelial staining only. Low-grade neoplasms showed lower transport rate (p < 0.01) but higher metabolic rate (p = 0.003) for AMT as compared to high-grade tumors. AMT metabolic rates were lower in tumor samples with no or minimal IDO expression as compared to those with widespread IDO staining (p = 0.017).

Conclusion: Low-grade tumors show widespread IDO expression, while IDO expression in high-grade brain tumors can be absent or largely confined to endothelial cells. AMT PET can be useful to identify brain tumors with different profiles of IDO expression, thus providing a useful imaging marker for emerging treatments targeting tumor IDO activity.

Figure 1

Immunohistochemistry comparing patterns of IDO expression in a low-grade (DNET) and high-grade tumor (glioblastoma multiforme, GBM). Positive IDO staining in tumor cells (A, arrows) and in perivascular tissue as well as neuropil (B) in the DNET (patient #4). In contrast, the GBM (patient #13) showed no staining in tumor cells or perivascular tissue (C, D). Positive IDO staining in endothelial cells in an anaplastic oligodendroglioma (patient #12) (E). Original magnification 40x in all images.

Figure 2

AMT PET scans and Patlak plots of a DNET (patient #4; A) and a glioblastoma multiforme (GBM, patient #13; B). Both tumors showed high AMT activity (arrows) on summed PET images (20–60 min after tracer injection), as shown on this figure. However, on the Patlak plot, the intercept, which represents volume of distribution (VD’), is higher for GBM compared to DNET. The metabolic rate of AMT, k₃’, was calculated as the ratio between the K-complex (slope of the Patlak curve) and VD’ and was much higher in the DNET than in the GBM (0.026 vs. 0.011). CP: tracer concentration in the blood, CT: tracer concentration in tumor tissue.