IMPS-34INNATE IMMUNOLOGICAL COMPENSATORY CONTROL OF GLIOMAGENESIS AND MALIGNANT TRANSFORMATION IN MURINE CD8α KNOCKOUT MODELS

BACKGROUND: The extent of CD8+ T cell infiltration has been shown to correlate with improved survival in patients with high-grade glioma. However, it is unknown how the CD8 effector cells influences gliomagenesis or the progression from low- to high-grade glioma. In this study we eliminated CD8 T cells in an otherwise immunocompetent model of glioma to study their effect on the initiation and malignant progression of glioma. METHODS: We backcrossed CD8α KO mice into the Ntv-a background and then induced endogenous gliomas in CD8α−/−/Ntv-a and CD8+/+/Ntv-a mice using co-expression of PDGFB and STAT3. Immune compensatory mechanisms were studied using ex vivo immune functional assays, immunohistochemistry, and flow cytometry. RESULTS: We verified the absence of CD8α T cells in CD8−/−/Ntv-a mice in peripheral blood, spleen and brain. Mice lacking CD8α T cells demonstrated no increase in glioma formation or grade compared to wild-type mice. The lack of CD8α T cells did not impact symptom free survival or the incidence of malignant degeneration. A compensatory increase of cytotoxic CD4+ T cells, CD19+ B cells, and NK 1.1+ cells was found systemically but did not traffic to the glioma microenvironment. In contrast, in the glioma-bearing CD8α−/−/Ntv-a mice, CD11b+ monocytes and Iba1+ macrophages were found to be over represented in the tumor microenvironment relative to glioma-bearing CD8 wild-type mice (P = 0.0001). The macrophages in the tumors from CD8α−/−/Ntv-a mice demonstrated increased TNF-alpha expression compared to those from wild-type mice indicating they are polarized to the M1 phenotype. CONCLUSIONS: Absence of the CD8α T cell population does not influence glioma formation or survival in an immunocompetent model. A compensatory increase in M1 macrophages was identified in tumor-bearing mice. These results indicate that the innate immune system effector response may play a key role in the control of gliomagenesis and the process of malignant degeneration.