Objective: Although mesenchymal stem cells (MSCs) have been investigated as a vector in stem cell-based therapy for malignant glioma, there has been a debate about the exact role of MSCs in tumor microenvironment. From an immunnological aspect, MSCs have been reported to inhibit T cell proliferation and to increase CD4+FoxP3+ regulatory T cells (Tregs). They also have been investigated as a potent immune suppressor in several clinical situations including autoimmune diseases. However, whether MSCs have an immune modulatory effect on Tregs in malignant gliomas or not has not been established.
Materials & methods: The author explored the impact of MSCs on freshly sorted CD4+ T cells or already activated Tregs in vitro to determine whether MSCs have different influences on naive T cells and Tregs. Furthermore, using orthotropic mouse glioma model, the author investigated MSC's effect on Tregs during tumor progression.
Results: The authors observed that MSCs decreased Treg conversion from naive T cells and Treg proliferation, without affecting the proportion of natural / induced Treg [nTreg; CD4+FoxP3+Helios+ / iTreg; CD4+FoxP3+Helios-]. When co-cultured with already activated Tregs, however, MSCs did not affect Treg induction and proliferation, but decreased the proportion of iTreg. With an intracranially implanted GL261 cell-based orthotropic mouse model, co-injection of MSCs with tumor cell implantation slightly increased Treg recruit into the tumor and decreased the proportion of iTreg. When MSCs were injected after glioma formation, there was no significant effect of MSCs on Treg recruit and phenotypic changes. Furthermore, there was a lower level of cytokine expressions including TGF-β, INF-γ, IL-2, and IL-1β in Tregs cocultured with MSCs than that in solely cultured Tregs. Increased gene expression of IL-6, CCL17, and TGF-β, or decreased gene expression of CCL2 in MSCs may be relevant to the phenotypic changes of cocultured Tregs.
Conclusions: This study demonstrates that MSCs mainly inhibit iTreg, leading to a relative increase of the proportion of nTregs in mouse glioma model, possibly throughIL-6 signaling pathway. With a better understanding for critical factors and immunological consequences for the altered Treg phenotype in glioma, future experiments will be needed to elucidate the immunological impact of MSCs on Tregs in malignant glioma.
Citation Format: Kyung-Sub Moon, Derek A. Wainwright, Irina V. Balyasnikova, Chung Kwon Kim, Yoo Seung Ko, Kyung Keun Kim, Maciej S. Lesniak. Immune modulatory effects of mesenchymal stem cells on regulatory T cells in mouse glioma model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-64. doi:10.1158/1538-7445.AM2014-LB-64