Invited lecture: Promoting immune rejection of tumors by blocking tryptophan catabolism by indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase
(2012) 26èmes Journées Franco-belges de Pharmacochimie — Location: Orléans, France (24.May.2012)
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- Abstract
- Immunotherapy is emerging as promising new approach for cancer therapy, with the first immunotherapy agents recently approved by the FDA, and many more in clinical development. However, it already appears that an important limitation to the efficacy of immunotherapy is the local immunosuppression that often develops at the tumor site. The study of the mechanisms of this local immunosuppression has therefore become a major topic in cancer research, the idea being that blocking such mechanisms should dramatically improve the success of cancer immunotherapy. We previously described a mechanism of tumoral immune resistance based on the expression by tumor cells of indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme that rapidly degrades tryptophan [1]. The resulting tryptophan depletion and accumulation of tryptophan catabolites is profoundly immunosuppressive, because T lymphocytes, which are the main effector cells for tumor rejection, are exquisitely sensitive to tryptophan deprivation and catabolites. We showed that blocking IDO activity with 1-methyl-L-tryptophan restored the rejection of IDO-expressing tumors by immune mice [1]. This has launched large efforts by many groups to discover and develop IDO inhibitors that can be used clinically [2-5]. Some compounds are currently in early phases of clinical trials. More recently, we became interested in unrelated enzyme that also degrades tryptophan along the kynurenine pathway, namely tryptophan 2,3-dioxygenase (TDO). TDO is normally expressed only in the liver, where it regulates systemic tryptophan levels. We found that enzymatically active TDO is expressed in a significant proportion of human tumors [6]. 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 [7]. Our results describe a new mechanism of tumoral immune resistance based on TDO expression and establish proof-of-concept for the use of TDO inhibitors in cancer therapy. 1. Uyttenhove, C., et al., Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat. Med., 2003. 9(10): p. 1269-1274. 2. Rohrig, U.F., et al., Rational design of indoleamine 2,3-dioxygenase inhibitors. J. Med. Chem., 2010. 53(3): p. 1172-1189. 3. Koblish, H.K., et al., Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors. Mol. Cancer Ther., 2010. 9(2): p. 489-498. 4. Dolusic, E., et al., Discovery and preliminary SARs of keto-indoles as novel indoleamine 2,3-dioxygenase (IDO) inhibitors. European journal of medicinal chemistry, 2011. 46(7): p. 3058-65. 5. Dolusic, E., et al., Indol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors. Bioorganic & medicinal chemistry, 2011. 19(4): p. 1550-61. 6. Pilotte, L., et al., Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc. Natl. Acad. Sci. U.S.A., 2012. 109(7): p. 2497-2502. 7. Dolusic, E., et al., Tryptophan 2,3-Dioxygenase (TDO) Inhibitors. 3-(2-(Pyridyl)ethenyl)indoles as Potential Anticancer Immunomodulators. J. Med. Chem., 2011. 54(15): p. 5320-5334.
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Van den Eynde, B. (2012). Invited lecture: Promoting immune rejection of tumors by blocking tryptophan catabolism by indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase. 26èmes Journées Franco-belges de Pharmacochimie, Orléans, France. https://hdl.handle.net/2078.5/51412