Sometimes (more often than I care to admit) I read papers because their titles intrigue me rather than I’m interested in the topic. The conjured image of tumours eating tryptophan [i] pulled me in and it turned out to be of more interest than I first thought, leading me into an area of which I was previously completely unaware.
For some time it has long been a matter for conjecture as to how cancers evade immune responses. It now seems the mystery is beginning to be unravelled and the elevated consumption of tryptophan by tumours plays a key role. Tryptophan is metabolised by a well established route (Figure 1) [ii].
The first enzymes on the pathway to niacin are the indoleamine 2,3-dioxygenase, IDO & IDO2. The publication by Opitz et al [iii] identified tryptophan dioxygenase (TDO) as an enzyme carrying out the same reaction. The downstream product, kynurenine (Kyn), was identified as the endogenous ligand for the human aryl hydrocarbon receptor. The up-regulation of tryptophan dioxygenase (TDO) was key to this discovery. The roles of IDO and IDO2 in cancer have been known for some time. What is new is the identification of TDO as a key enzyme in this process as well.
Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion (Figure 2). Binding of Kyn to the AHR leads to translocation of the receptor to the nucleus and upregulation of genes promoting cell growth. Additionally Kyn inhibits the activation of T-cells and dentritic cells and regulatory B-cells. The upshot of this is to down-regulate the immune system and prevent it from attacking the growing tumour.
The hypothesis that IDO inhibition might enhance the efficacy of cancer treatments is is being currently evaluated. Results from in vitro and in vivo studies have suggested an improvement of the efficacy of therapeutic vaccination or chemotherapy by concomitant administration of an IDO inhibitor [v].
Inhibitors of both IDO [vi] and TDO[vii] are beginning to appear in the scientific literature, primarily from the Drug Design and Discovery Centre, University of Namur, Belgium. At present these compounds are structurally related to tryptophan and of moderate potency (Figure 5 & 6). The most potent TDO inhibitor (Figure 4) possessed a TDO IC50 2mM, was non-toxic (TD50 >400mM) and was soluble (>300uM). The compound was advanced to an in vivo efficacy study to decipher the exact role of TDO in cancer immunosuppression. Mice were immunized and challenged with compound administered in the drinking water. Systemic treatment of immunized mice with compound at 160 mg/kg/day prevented the growth of TDO-expressing P815 tumour cells with no obvious signs of toxicity.
[i] Cancer: Why tumours eat tryptophan, Prendergast George C, Nature (2011), 478(7368), 192-4
[iii] An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor, Opitz, Christiane A.; Litzenburger, Ulrike M.; Sahm, Felix; Ott, Martina; Tritschler, Isabel; Trump, Saskia; Schumacher, Theresa; Jestaedt, Leonie; Schrenk, Dieter; Weller, Michael; Nature (2011), 478(7368), 197-203
[iv] Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido, Balachandran, V.P. et al. Nat. Med. 17, 1094–1100 (2011).
[v] Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase, Uyttenhove, C.; Pilotte, L.; Theate, I.; Stroobant, V.; Colau, D.; Parmentier, N.; Boon, T.; Van den Eynde, B. J. Nat. Med. 2003, 9, 1269. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy, Muller, A. J.; DuHadaway, J. B.; Donover, P. S.; Sutanto-Ward, E.; Prendergast, G. C. Nat. Med. 2005, 11, 312. Indoleamine 2,3-dioxygenase in cancer: targeting pathological immune tolerance with small-molecule inhibitors, Muller, A. J.; Malachowski, W. P.; Prendergast, G. C. Expert Opin. Ther. Targets 2005, 9, 831. Marrying immunotherapy with chemotherapy: why say IDO? Muller, A. J.; Prendergast, G. C. Cancer Res. 2005, 65, 8065. Indoleamine 2,3-dioxygenase in immune suppression and cancer, Muller, A. J.; Prendergast, G. C. Curr. Cancer Drug Targets 2007, 7, 31.
[vi] Indol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors, Dolusic, Eduard; Larrieu, Pierre; Blanc, Sebastien; Sapunaric, Frederic; Norberg, Bernadette; Moineaux, Laurence; Colette, Delphine; Stroobant, Vincent; Pilotte, Luc; Colau, Didier; et al, Bioorganic & Medicinal Chemistry (2011), 19(4), 1550-1561
[vii] Tryptophan 2,3-Dioxygenase (TDO) Inhibitors. 3-(2-(Pyridyl)ethenyl)indoles as Potential Anticancer Immunomodulators, Dolusic, Eduard; Larrieu, Pierre; Moineaux, Laurence; Stroobant, Vincent; Pilotte, Luc; Colau, Didier; Pochet, Lionel; Van den Eynde, Benoit; Masereel, Bernard; Wouters, Johan; et al, Journal of Medicinal Chemistry (2011), 54(15), 5320-5334