Indoleamine 2,3 Dioxygenase (IDO) as a Mediator of Myeloid Derived Suppressor Cell Function in Breast Cancer
Abstract
Therapies aimed at activating breast cancer patient's 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 BALB/c 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 (4T1/IL-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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 31, 2009
- Accession Number
- ADA515799
Entities
People
- Linglin Yang
Organizations
- University of Maryland, Baltimore County