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M.S., Wuhan University - 2006
Thesis Advisor: Yufang Shi, Ph.D.
Graduate Program in Microbiology & Molecular Genetics
Child Health Institute of New Jersey
Tuesday, November 26, 2013
Mesenchymal stem cells (MSCs) are a group of multipotent stem cells, existing in almost all tissues and are believed to be critical in the regulation of the tissue immune microenvironment and in tissue regeneration. The versatile functions of MSCs ranging from immune modulation to disease treatment and regenerative medicine have gained a lot of attention, especially on their contribution to tumor progression. Interestingly, there is no consensus on the effect of MSCs on tumor growth owing to different sources of MSCs. To provide better understanding of the immune modulation by MSCs on tumor microenvironment, we employed different tumor models and different sources of MSCs to test the effect of MSCs on tumor growth. Firstly, we established a novel humanization system to model human MSCs that employ Murine iNOS-/- MSCs constitutively or inducibly expressing human IDO. In this system, inducible IDO expression is driven by the mouse iNOS promoter that can be activated by inflammatory cytokine stimulation in a similar fashion as the human IDO promoter. These humanized MSCs (MSC-IDO) were able to suppress lymphocyte proliferation in vitro and promote tumor growth in vivo. These effects were reversible by 1-methyltryptophan, an IDO inhibitor. These IDO-expressing MSCs dramatically reduced tumor-infiltrating CD8+ T cells and B cells. Therefore, interventional targeting of IDO activity could provide a novel strategy to regulate tumor immunity in humans. Secondly, we examined the effect of nicotine treated MSCs on tumor colonization by employing B16-F10 experimental metastasis tumor model. MSCs were treated nicotine, an addictive component of tobacco, and these treatment inhibited MSC differentiation into adipocytes and osteoblasts. We also found that these nicotine treated MSCs promoted B16-F10 tumor growth and that this tumor promotion effect was through the regulation of C-X-C chemokine receptor type 4 (CXCR4), a receptor for the C-X-C chemokine CXCL12/SDF-1 because the effect was abolished by the administration of CXCR4 antagonist AMD-3100. Lastly, we found that in Kb-/-Db-/- mice the administration of wild type MSCs inhibited tumor growth whereas it has no effect in wild type mice. In vivo tumor immune cell population analysis demonstrated that this tumor inhibitory effect was due to the increase of infiltrates of non-classical CD8+ T cells in tumor tissue. In all, our study provided new insight about the role of MSCs in tumor growth and their immune modulation in tumor microenvironment.