|KIM, HYUNGGOON - University Of Alabama
|O'BRIEN, REBECCA - University Of California
|JADUS, MARTIN - National Jewish Health
|GILLESPIE, YANCEY - University Of Alabama
|CLOUD, GRETCHEN - University Of Alabama
|HOA, NEIL - University Of Alabama
|LANGFORD, CATHERINE - University Of Alabama
|LOPEZ, RICHARD - University Of Alabama
|HARKINS, LUALHATI - University Of Alabama
|LAMB, LAWRENCE - University Of Alabama
Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/17/2015
Publication Date: 5/8/2015
Citation: Beck, B.H., Kim, H., O'Brien, R., Jadus, M.R., Gillespie, Y.G., Cloud, G.A., Hoa, N.T., Langford, C.P., Lopez, R.D., Harkins, L., Lamb, L.S. 2015. Dynamics of circulating gamma delta T cell activity in an immunocompetent mouse model of high-grade glioma. PLoS One. p. 1-15.
Interpretive Summary: Glioblastoma multiforme (GBM) is a type of brain cancer that is difficult to treat and has a very low survival rate, making new therapies desperately needed. Previously, we determined that a specific group of immune cells, called Gamma Delta T cells (pronounced gamma delta-T cells), were capable of killing GBM tumor cells, making them a promising target for a potential therapy. However, in patients with GBM the numbers of gamma delta''T cells in blood were very scarce. In the present study, to better understand this scarcity of gamma delta''T cells in patients with GBM, we used a mouse model of GBM (develops disease in a similar manner to humans) to track the number and condition of gamma delta''T cells during the progression of GBM. We found that after implantation of GBM tumor cells in the brains of mice, the numbers of 'T cells in mouse blood sharply increased. However, of these gamma delta T cells that had increased in number, many showed a marker on their surface indicating that they were undergoing cell death. Next, we treated mice bearing GBM tumors with large numbers of gamma delta''T cells and found that gamma delta''T cells could limit the scope of tumor growth within the brain, but not improve overall survival. These findings suggest that gamma delta''T cells are stimulated to grow in mice with GBM, but may be suffering from a type of GBM-induced cell death. The results of this study contribute to our understanding of GBM, and will be used to design better therapies for patients suffering from GBM.
Technical Abstract: Human gamma delta T cells are potent effectors against glioma cell lines in vitro and in human/mouse xenograft models of glioblastoma, however, this effect has not been investigated in an immunocompetent mouse model. In this report, we established GL261 intracranial gliomas in syngeneic WT C57BL/6 mice and measured circulating gamma delta T cell count, phenotype, Vgamma/Vdelta repertoire, tumor histopathology, NKG2D ligands expression, and T cell invasion at day 10-12 post-injection and at end stage. Circulating gamma delta T cells transiently increased and upregulated Annexin V expression at post-tumor day 10-12 followed by a dramatic decline in gamma delta T cell count at end stage. T cell receptor repertoire showed no changes in Vgamma1, Vgamma4, Vgamma7 or Vdelta1 subsets from controls at post-tumor day 10-12 or at end stage except for an end-stage increase in the Vdelta4 population. Approximately 12% of gamma delta T cells produced IFN-gamma. IL-17 and IL-4 producing gamma delta T cells were not detected. Tumor progression was the same in TCRdelta-/- C57BL/6 mice as that observed in WT mice, suggesting that gamma delta T cells exerted neither a regulatory nor a sustainable cytotoxic effect on the tumor. WT mice that received an intracranial injection of gamma delta T cells 15 min following tumor placement showed evidence of local tumor growth inhibition but this was insufficient to confer a survival advantage over untreated controls. Taken together, our findings suggest that an early nonspecific proliferation of gamma delta T cells followed by their depletion occurs in mice implanted with syngeneic GL261 gliomas. The mechanism by which gamma delta T cell expansion occurs remains a subject for further investigation of the mechanisms responsible for this immune response in the setting of high-grade glioma.