Breakdown of tryptophan to kynurenine by the enzyme indoleamine-2,3-dioxygenase (IDO) inhibits T cell responses and promotes immune tolerance. Tryptophan degradation by IDO in tumor cells is associated with immune evasion and increased tumor growth (see commentary by Prendergast). Thus, better understanding of how tryptophan catabolism affects immune responses might help to develop anticancer therapies. Opitz et al. found that cultured human glioma cell lines and glioma-initiating cells degraded tryptophan and produced large quantities of kynurenine. Knockdown of IDO isoforms in these cells had no effect on tryptophan metabolism; rather, knockdown of another tryptophan-degrading enzyme, TDO, blocked production of kynurenine. Immunohistochemical analysis showed that the abundance of TDO correlated with malignancy in human brain tumors. The amount of kynurenine produced by glioma cells correlated with inhibition of the proliferation of cocultured T cells. Knockdown of TDO in glioma cells restored T cell proliferation, whereas T cell proliferation was inhibited by the addition of exogenous kynurenine. The growth of TDO knockdown tumors implanted in the brains of nude mice was impeded compared to that of tumors proficient in TDO. Microarray analysis of kynurenine-treated glioma cells revealed the enhanced expression of many aryl hydrocarbon receptor (AHR)–responsive genes. The AHR is a transcription factor that responds to xenobiotic compounds, such as dioxin, to suppress immune responses and stimulate tumorigenesis. AHR-responsive gene expression in glioma cells was decreased when TDO was knocked down, suggestive of autocrine AHR signaling. However, when injected into Ahr-deficient mice, Tdo-expressing tumor cells exhibited attenuated growth, suggesting that paracrine AHR signaling was also required for tumor progression. Microarray analysis showed that expression of TDO correlated with that of AHR-responsive genes in many different cancer types, and high expression of TDO, AHR, or the AHR-responsive gene CYP1B1 correlated with poor survival of glioma patients. Together, these data suggest that TDO-derived kynurenine acts in an autocrine and paracrine fashion through the AHR to promote tumor growth.
C. A. Opitz, U. M. Litzenburger, F. Sahm, M. Ott, I. Tritschler, S. Trump, T. Schumacher, L. Jestaedt, D. Schrenk, M. Weller, M. Jugold, G. J. Guillemin, C. L. Miller, C. Lutz, B. Radlwimmer, I. Lehmann, A. von Deimling, W. Wick, M. Platten, An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011). [PubMed]
G. C. Prendergast, Why tumours eat tryptophan. Nature 478, 192–194 (2011). [Online Journal]