|Gillepsie, G - University Of Alabama|
|Lopez, Richard - University Of Alabama|
|Cloud, Gretchen - University Of Alabama|
|Langford, Cathy - University Of Alabama|
|Kim, Hyung - University Of Alabama|
|Harkins, Luahati - University Of Alabama|
|Lamb, Lawrence - University Of Alabama|
Submitted to: American Association of Cancer Research
Publication Type: Abstract Only
Publication Acceptance Date: 2/7/2012
Publication Date: 4/1/2012
Citation: Beck, B.H., Gillepsie, G.Y., Lopez, R.D., Cloud, G.A., Langford, C., Kim, H., Harkins, L., Lamb, L.S. 2012. Circulating gamma delta T cells are activated and depleted during progression of high-grade gliomas: Implications for gamma delta T cell therapy of GBM [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association of Cancer Research, March 31 - April 4, 2012, Chicago, Illinois. Philadelphia (PA). American Association of Cancer Research. 72(8 Supplement):530.
Technical Abstract: Glioblastoma multiforme (GBM) remains frustratingly impervious to any existing therapy. We have previously shown that GBM is sensitive to recognition and lysis by ex vivo activated gamma delta T cells, a minor subset of lymphocytes that innately recognize autologous stress-associated target antigens via the T cell receptor and/or NKG2D. However, circulating gamma delta T cell counts and function are significantly reduced in patients with GBM. We sought to determine the role of gamma delta T cells in the immune response to high-grade gliomas in C57BL/6 mice bearing GL261 cell line-derived intracranial gliomas. Examination of mice 15 days after intracranial tumor placement and prior to development of neurologic symptoms revealed small infiltrating high-grade gliomas near the injection site. Concurrently, the peripheral blood gamma delta T cell count was significantly increased when compared to control mice that received only the methylcellulose vehicle (p=0.0003). T cell expansion was confined to the gamma delta T cell compartment, and a substantial proportion of gamma delta T cells in tumor-bearing mice expressed Annexin-V (20%-45%) indicating progression to apoptosis. Annexin-V expression in control mice was confined to 2-5% of gamma delta T cells, significantly less than tumor-bearing mice (p<0.0001). GL261-derived tumors expressed gamma delta T cell target stress-associated NKG2D ligands H60, MULT-1 and RAE-1, yet gamma delta T cells did not infiltrate the intracranial tumors. In a separate experiment, we found no survival advantage between wild-type (WT) mice over gamma delta T cell-deficient (C57BL/6delta-/-) tumor-bearing mice. Based on this observation that activated gamma delta T cells did not invade the tumor, we treated mice with a stereotactic intracranial injection of 1.5 x 106 ex vivo expanded/activated gamma delta T cells approximately 15 minutes following placement of 5 x 106 GL261 glioma cells. Mice that received intracranial gamma delta T cells were protected from tumor development at site of injection, although distant tumors did eventually form. These data suggest that gamma delta T cells are stimulated in glioma-bearing mice and that depletion in gamma delta T cells observed in mouse glioma models and human GBM are likely due to activation-induced cell death in response to the tumor. Activated gamma delta T cells do not traffic to the tumor parenchyma; however, an antitumor effect can be achieved by direct placement of ex vivo activated gamma delta T cells in the vicinity of microscopic disease, suggesting a potential post-resection strategy for treatment of minimal residual GBM.