Tumor immune evasion mediated by IDO

Tumors actively create a state of immunologic tolerance toward themselves. One mechanism that may contribute to this condition of pathologic tolerance is the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). Host dendritic cells expressing immunosuppressive IDO are found in tumor-draining lymph nodes, and IDO can also be expressed by tumor cells themselves. Either or both of these sites of IDO expression might serve to inhibit the immune response to tumors. Pharmacologic strategies to block the IDO pathway may be useful in helping to break the pre-established state of tolerance that exists in tumor-bearing hosts. Consistent with this possibility, in murine models the IDO inhibitor 1-methyl-tryptophan (1MT) has demonstrated significant synergy with several clinically relevant chemotherapeutic agents, initiating immune-mediated tumor regression following conventional chemotherapy. IDO inhibitor drugs may also reduce unwanted collateral immunosuppression by toll-like receptor (TLR) ligands such as CpG oligodeoxynucleotides, which can be potent inducers of IDO activity. Combination with IDO inhibitors may reduce suppression and the enhance efficacy of IDO-inducing agents such as CpG. IDO inhibitor drugs are thus potential immunomodulatory agents for cancer immunotherapy, and may display synergistic activity in combination both with chemotherapy and with other forms of immunotherapy.