Blocking IDO activity to enhance anti-tumor immunity.
Tumors express potentially immunogenic antigens, yet the immune response to these antigens is typically profoundly suppressed. Patients with established tumors behave as if they were functionally tolerant to any antigens associated with the tumor. This tolerance reflects a process of active immune suppression elicited by the tumor, and represents a critical barrier to successful anti-tumor immunotherapy. Indoleamine 2,3-dioxygenase (IDO) is a natural immunoregulatory mechanism contributes to immune suppression and tolerance in a variety of settings. In tumor-bearing hosts, animal models suggest that tumor-induced IDO helps create a tolerogenic milieu within the tumor and the associated tumor-draining lymph nodes. IDO directly suppresses the proliferation and differentiation of effector T cells, and markedly enhances the suppressor activity of regulatory T cells (Tregs). Together, these effects contribute to the inability of the immune system to respond effectively to tumor antigens. Treatment of tumor-bearing animals with IDO-inhibitor drugs enhances anti-tumor immune responses, and IDO-inhibitors are synergistic with a variety of chemotherapeutic drugs, anti-tumor vaccines and other immunotherapy. Strategies to pharmacologically inhibit IDO may thus enhance immune-mediated responses following conventional chemotherapy, and may be synergistic with other forms of immunotherapy.
Immunotherapy Center, Room CN-4141, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, USA. dmunn@georgiahealth.edu
David H
DH
Munn
D019496:Cancer Vaccines / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007108:Immune Tolerance; D007167:Immunotherapy; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology* / Q000601:surgery / Q000628:therapy
D019496:Cancer Vaccines; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase