Indoleamine 2,3-dioxygenase and tumor-induced immune suppression

Tumors express antigens to which the immune system should, in principle, be able to respond. Yet the immune response to tumors is usually weak or absent, and is seldom curative even with the best available immunotherapy. Functionally, patients with tumors behave as if they were tolerant to their tumor antigens. This state of acquired functional tolerance must be overcome in order for immunotherapy of cancer to succeed. Expression of indoleamine 2,3-dioxygenase (IDO) is a molecular mechanism that contributes to acquired peripheral tolerance in the immune system, and has been implicated in tumor-induced tolerance. Animal models suggest that IDO helps create an immunosuppressive and tolerance-inducing milieu within the tumor and the associated tumor-draining lymph nodes. IDO directly suppresses responses by effector T cells, and also creates potent bystander suppression by enhancing the inhibitory activity of local regulatory T cells (Tregs). In preclinical models, IDO-inhibitor drugs are synergistic with a number of chemotherapeutic agents, and enhance the efficacy of anti-tumor vaccines. Further, because IDO is induced in a variety of inflammatory settings, IDO may inadvertently act as an undesirable counter-regulatory antagonist that limits the efficacy of beneficial immune activators, such as vaccine adjuvants. Strategies to block IDO may thus be synergistic with chemotherapy, and may enhance the effectiveness of other forms of anti-tumor immunotherapy. Orally-bioavailable small-molecule inhibitors of the IDO pathway, such as 1-methyl-d-tryptophan, are now entering clinical trials.