Mesenchymal stem cells use IDO to regulate immunity in tumor microenvironment

Abstract

Mesenchymal stem cells (MSC) are present in most, if not all, tissues and are believed to contribute to tissue regeneration and the tissue immune microenvironment. Murine MSCs exert immunosuppressive effects through production of inducible nitric oxide synthase (iNOS), whereas humanMSCs use indoleamine 2,3-dioxygenase (IDO). Thus, studies ofMSC-mediated immunomodulation inmicemay not be informative in the setting of human disease, although this critical difference has been mainly ignored. To address this issue, we established a novel humanized system to model human MSCs, using murine iNOS/MSCs that constitutively or inducibly express an ectopic human IDO gene. In this system, inducible IDO expression is driven by amouse iNOS promoter that can be activated by inflammatory cytokine stimulation in a similar fashion as the human IDO promoter. These IDO-expressing humanized MSCs (MSC-IDO) were capable of suppressing T-lymphocyte proliferation in vitro. In melanoma and lymphoma tumormodels,MSC-IDOpromoted tumor growth in vivo, an effect that was reversed by the IDOinhibitor 1-methyl-tryptophan. We found that MSC-IDO dramatically reduced both tumor-infiltrating CD8+ T cells and B cells. Our findings offer an important newline of evidence that interventional targeting of IDOactivity could be used to restore tumor immunity in humans, by relieving IDO-mediated immune suppression of MSCs in the tumor microenvironment as well as in tumor cells themselves. © 2013 American Association for Cancer Research.