Malignant gliomas represent a significant class of central nervous system (CNS) tumors and are relatively incurable. The 5-year survival rate is 2%, despite treatment with surgery, radiation and chemotherapy. Immunotherapeutic approaches aimed at the activation of tumor-specific T cells, are actively being investigated in pre-clinical and clinical studies for the treatment of gliomas. In our studies in the activation of glioma-specific T cells, we have recently reported that s.c. vaccination of rats bearing a T9 glioma (T9+vacc.) or the implantation of IL-2 secreting T9 cells effectively activates T cells which cross the blood brain barrier and infiltrate the tumor. However, the T cells are tolerant and the tumor rapidly progresses. In contrast, s.c. tumors are rejected. We identified a population of myeloid suppressor cells (MSC) which localize to the intracranial tumor and inhibit cell function. We have reported that MSC mobilization can be induced in other experimental glioma models, but does not occur when nude rats are used in the T9+vacc. model. We hypothesize that factors from activated T cells in the glioma and possibly the CNS parenchyma elicit the rapid mobilization of MSC which subsequently localize to the tumor and suppress T cell function, thereby contributing to brain-tumor associated immunosuppression. To test this hypothesis, we will: 1) use chimeric rats to establish that MSC are bone marrow derived; 2) selectively deplete rats of T cell subsets to identify T cell subsets involved with MSC mobilization; 3) use protein specific arrays to identify factors involved with MSC mobilization; 4) identify mechanisms MSC mediated T cell inhibition; 5) assess the involvement of regulatory T cells in our glioma model; and 6) analyze human glioma tissue for the presence of MSC. We believe that MSC may play an immuno-regulatory role in the CNS to mediate T cell activity. Therefore, MSC may represent a significant obstacle to the successful immunotherapy for gliomas. The results of the proposed studies will advance our understanding of brain-tumor associated immunosuppression which will lead to more successful therapeutic approaches for the treatment of brain tumor patients, particularly in strategies employing the activation of T cells, making these studies highly significant and timely. ? ? ? ?
| Jia, Wentao; Jackson-Cook, Colleen; Graf, Martin R (2010) Tumor-infiltrating, myeloid-derived suppressor cells inhibit T cell activity by nitric oxide production in an intracranial rat glioma + vaccination model. J Neuroimmunol 223:20-30 |
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