Indoleamine 2,3 Dioxygenase (IDO) as a Mediator of Myeloid Derived Suppressor Cell Function in Breast Cancer

Therapies aimed at activating breast cancer patients adaptive immune response to metastatic tumor cells are being developed however, most patients with advanced disease are immune suppressed, making it unlikely that active immunotherapies will be effective. Myeloid-derived suppressor cells MDSC are a major player in tumor-induced immune suppression seen in many patients and experimental animals with breast cancer and inhibit immunity by blocking T cell activation. Indoleamine 2,3 dioxygenase IDO, a tryptophan degradation enzyme, also contributes to immune escapes by suppressing T cell activation. To determine if MDSC activity is regulated by IDO, wild type BALBc and IDO-- mice were challenged with 4T1 mammary carcinoma cells. MDSC from IDO-- mice were less suppressive than MDSC from IDO mice, and treatment with the IDO inhibitor 1-D-MT partially restored T cell proliferation. Western blots demonstrated that MDSC do not contain IDO, suggesting that IDO indirectly affects MDSC suppression. IDO-induced tryptophan starvation is known to act through the IL-6 signaling pathway by activating nuclear factor-IL-6. Since IL-6 is an inducer of MDSC, we tested MDSC from IDO mice carrying IL-6 transfected 4T1 cells 4T1IL-6. 4T1-IL-6-induced MDSC from IDO-- mice were equally suppressive to 4T1-induced MDSC from IDO mice demonstrating that IL-6 overcomes IDO deficiency and restores MDSC suppression. We conclude that IDO enhances MDSC suppressive activity by inducing IL-6 production which then activates MDS.