Human bone marrow-derived mesenchymal stem cells suppress human glioma growth through inhibition of angiogenesis.

Tumor tropism of human bone marrow-derived mesenchymal stem cells (MSC) has been exploited for the delivery of therapeutic genes for anticancer therapy. However, the exact contribution of these cells in the tumor microenvironment remains unknown. In this study, we examined the biological effect of MSC on tumor cells. The results showed that MSC inhibited the growth of human glioma cell lines and patient-derived primary glioma cells in vitro. Coadministration of MSC and glioma cells resulted in significant reduction in tumor volume and vascular density, which was not observed when glioma was injected with immortalized normal human astrocytes. Using endothelial progenitor cells (EPC) from healthy donors and HUVEC endothelial cells, the extent of EPC recruitment and capacity to form endothelial tubes was significantly impaired in conditioned media derived from MSC/glioma coculture, suggesting that MSC suppressed tumor angiogenesis through the release of antiangiogenic factors. Further studies using antibody array showed reduced expression of platelet-derived growth factor (PDGF)-BB and interleukin (IL)-1ß in MSC/glioma coculture when compared with controls. In MSC/glioma coculture, PDGF-BB mRNA and the corresponding proteins (soluble and membrane bound forms) as well as the receptors were found to be significantly downregulated when compared with that of glioma cocultured with normal human astrocytes or glioma monoculture. Furthermore, IL-1ß, phosphorylated Akt, and cathepsin B proteins were also reduced in MSC/glioma. Taken together, these data indicated that the antitumor effect of MSC may be mediated through downregulation of PDGF/PDGFR axis, which is known to play a key role in glioma angiogenesis. STEM Cells2013;31:146-155.

Nonmyeloablative allogeneic stem cell transplantation for nasopharyngeal carcinoma.

We present a case of a patient with metastatic nasopharyngeal carcinoma who failed two lines of palliative combination chemotherapy and was treated with allogeneic nonmyeloablative stem cell transplantation (NST). This patient achieved a durable tumor response, dramatic relief of his symptoms, and elimination of tumor in his bone marrow-an effect likely achieved via a graft-versus-tumor response. Although NST has been explored previously in solid tumors, such as renal cell carcinoma and breast cancer, it has not been widely explored in nasopharyngeal carcinoma. We also present data from a flow cytometric immune analysis and cytokine enzyme-linked immunosorbent assay analysis in the pre- and post-NST period.

G-CSF induces a potentially tolerant gene and immunophenotype profile in T cells in vivo.

G-CSF can induce functional immune tolerance in man. In this study, purified T cells from G-CSF-mobilized peripheral blood stem cell (PBSC) donors were analysed by gene expression profiling and immunophenotyping. Results suggested a predominantly immune tolerant profile with upregulation of genes related to Th2 and Treg cells, downregulation of genes associated with Th1 cells, cytotoxicity, antigen presentation and graft-versus-host disease (GVHD) and overexpression of negative regulators of Th17 differentiation. Immunophenotyping revealed that during G-CSF exposure donors had reduced levels of T cells with a Th17 phenotype (CD4+IL-17A+CCR6+IL-23R+), more than three times lower compared to normal controls. G-CSF also led to increased levels of CD4+CD25highCD45RO+ Treg cells. Furthermore, mRNA levels of RORgammat, a Th17-specific transcription factor, decreased in T cells isolated from G-CSF-mobilized PBSC harvests. Th17 cells have been implicated in autoimmune diseases and GVHD pathophysiology. Our study is the first to report the effect of G-CSF on the Th17 subpopulation.

Fluctuating lymphocyte chimerism, tolerance and anti-tumor response in a patient with refractory lymphoma receiving nonmyeloablative conditioning and a haploidentical related allogeneic bone marrow transplant.

A 51-year-old patient with refractory non-Hodgkin lymphoma (NHL) received non-myeloablative conditioning and a two of six (A, B, DR) human leucocyte antigen (HLA) mismatched donor BMT. Post-BMT lymphocytes showed fluctuating T- and natural killer (NK)-cell chimerism, which culminated in mainly donor lymphocytes by Day + 100. Changes in lymphocyte chimerism correlated with anti-donor and anti-host responses in mixed lymphocyte reaction (MLR). On Day + 100, a strong anti-host response was observed in MLR in the absence of graft-versus-host disease (GVHD), together with near complete regression of the patient's lymphoma. A mild chronic GVHD later developed and, eventually, by 680 days post-BMT, the lymphoma had relapsed and MLR reflected a state of global immune unresponsiveness. These observations demonstrate evolving host-versus-graft and graft-versus-host tolerance that correlates with fluctuating lymphoid chimerism and graft-versus-lymphoma (GVL) effects, in the absence of severe GVHD. Eventual lymphoma relapse temporally correlated with a generalised immunosuppressed state.