Invited lecture: Boosting cancer immunotherapy by blocking tryptophan degradation
(2012) 7th Annual HBGP Symposium, “Immunity and Inflammation in Disease” — Location: Helsinki, Finland (7.June.2012)
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- Abstract
- Building up on the discovery of tumor antigens two decades ago, immunotherapy is currently emerging as a promising new approach for cancer therapy, with the first immunotherapy agents recently approved by the FDA, and many more in clinical development. Tumor antigens recognized by cytolytic T lymphocytes consist of peptides presented by MHC class I molecules. The study of these peptides, which mostly result from the degradation of intracellular proteins by the proteasome, also enabled uncovering unexpected post-translational modifications, including the splicing of peptides by the proteasome (1-3). Notwithstanding those recent clinical successes, 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 (4). 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 (4). This has launched large efforts by many groups to discover and develop IDO inhibitors that can be used clinically (5-8). Some compounds are currently in early phases of clinical trials. More recently, we became interested in an 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 (9). 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 (9, 10). 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.
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Van den Eynde, B. (2012). Invited lecture: Boosting cancer immunotherapy by blocking tryptophan degradation. 7th Annual HBGP Symposium, “Immunity and Inflammation in Disease”, Helsinki, Finland. https://hdl.handle.net/2078.5/48336