Mesenchymal Stem Cells Employ IDO to Regulate Immunity in Tumor Microenvironment
Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels, en exprimant l'enzyme IDO, les cellules souches mésenchymateuses régulent la prolifération des lymphocytes T dans le micro-environnement tumoral
Mesenchymal stem cells (MSCs) 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 the nitric oxide synthase iNOS, while human MSCs utilize indoleamine 2,3-dioxygenase (IDO). Thus, studies of MSC-mediated immunomodulation in mice may 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, employing murine iNOS-/- MSCs that constitutively or inducibly express an ectopic human IDO gene . In this system, inducible IDO expression is driven by a mouse 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 tumor models, MSC-IDO promoted tumor growth in vivo, an effect that was reversed by the IDO inhibitor 1-methyl-tryptophan. We found that MSC-IDO dramatically reduced both tumor-infiltrating CD8+ T cells and B cells. Our findings offer an important new line of evidence that interventional targeting of IDO activity 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.
Cancer Research 2014