Invited lecture: Blocking tryptophan catabolism to boost anti-tumor immune responses
(2013) 42nd Annual Meeting of the Japanese Society for Immunology — Location: Chiba, Japan (11.December.2013)
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- Abstract
- Cancer immunotherapy is currently gaining momentum, with the recent approval of the first immunotherapy agents, and many more in clinical development. Yet, it is already clear that an important limitation to the efficacy of immunotherapy is the local immunosuppression that often develops at the tumor site, particularly in advanced patients. Studying the mechanisms of this local immunosuppression has therefore become of utmost importance, the idea being that blocking such mechanisms should dramatically improve the success of cancer immunotherapy. One such mechanism is tryptophan catabolism, which can be exerted by indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme that rapidly degrades tryptophan along the kynurenine pathway 1. The resulting tryptophan depletion and accumulation of tryptophan catabolites is profoundly immunosuppressive. IDO is an interferon-gamma-inducible gene, which is expressed constitutively in a number of human tumors. It is also expressed in mature dendritic cells, and IDO-expressing dendritic cells were found enriched in murine tumor-draining lymph nodes. In preclinical models, pharmacological inhibitors of IDO activity can boost the immune rejection of tumors. This has triggered large efforts by many groups to discover and develop IDO inhibitors for clinical use. The first clinical trials of IDO inhibitors in cancer patients have started. Tryptophan 2,3-dioxygenase (TDO) is another enzyme that also degrades tryptophan along the kynurenine pathway. TDO is normally expressed in the liver, where it regulates systemic tryptophan levels. But TDO is also expressed in a number of human tumors 2. In a preclinical model, TDO expression by tumors prevented their rejection by immunized mice. We developed a novel TDO inhibitor, which, upon systemic treatment, restored the ability of mice to reject TDO-expressing tumors 2, 3. TDO therefore represents another immunosuppressive enzyme that can be targeted to boost the efficacy of cancer immunotherapy in cancer patients. References 1. Uyttenhove, C. et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat. Med. 9, 1269-1274 (2003). 2. Pilotte, L. et al. Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc. Natl. Acad. Sci. U.S.A. 109, 2497-2502 (2012). 3. Dolusic, E. et al. Tryptophan 2,3-Dioxygenase (TDO) Inhibitors. 3-(2-(Pyridyl)ethenyl)indoles as Potential Anticancer Immunomodulators. J. Med. Chem. 54, 5320-5334 (2011).
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Van den Eynde, B. (2013). Invited lecture: Blocking tryptophan catabolism to boost anti-tumor immune responses. 42nd Annual Meeting of the Japanese Society for Immunology, Chiba, Japan. https://hdl.handle.net/2078.5/51347