IDO Pathway: Effect on Foxp3⁺ Tregs and Cancer

Indoleamine 2,3-dioxygenase (IDO) is a metabolic pathway implicated in a number of settings that lead to acquired peripheral tolerance. IDO may also participate in the functional tolerance of the immune system towards tumors. Foxp3⁺ Tregs are major contributors to tumor-induced immune suppression, and emerging evidence links the IDO pathway with Treg activation. IDO-expressing dendritic cells (DCs) can drive the differentiation of naive CD4⁺ T cells into Foxp3⁺ Tregs. IDO⁺ DCs can also directly activate mature, preformed Tregs to mediate enhanced suppression. In experimental models, IDO also stabilizes the suppressive Treg phenotype and prevents inflammation-induced reprogramming of Tregs into pro-inflammatory (T-helper-like) cells. IDO may thus represent an important regulatory checkpoint that enhances Treg activity in tumor-bearing hosts. Drugs that target the IDO pathway may assist in reducing Treg-mediated suppression during antitumor immunotherapy.