THE IMPACT OF OXYGEN TENSION ON CD8+ T CELL FUNCTION AND INTERACTION WITH GLIOMA CELLS

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Abstract

BACKGROUND: (blind field) METHODS: We studied a clonal population of gp100 antigen-specific CD8+ T cells from pmel-1 mice and the assays were performed in vitro in a hypoxia work station. 5% O2 corresponds to the expected oxygen fraction in lymph nodes where most T cells are physiologically primed. Interactions with glioma were modelled using gp100-expressing GL261 glioma cells. RESULTS: In vitro activation of CD8+ T cells at physiologic O2 fraction generated cytotoxic T cells (CTLs) with higher effector functions (cytotoxicity and IFN-γ secretion) than at the 21% used in conventional culture. After activating CD8+ T cells at different O2 fractions, we then studied their function under hypoxia (1% O2), mimicking conditions after migration and infiltration of the glioma. Co-culture of CTLs and GL261 glioma cells at 1% O2 resulted in efficient tumor cell lysis, indicating that in the short term, hypoxia does not inhibit the killing capacities of CTLs, and that glioma cells are susceptible to immune-mediated elimination in this microenvironment. However, we also measured negative effects of hypoxia on anti-tumour immunity: CTL secretion of the immunosuppressive cytokine IL-10 and reduced T cell proliferation. CONCLUSIONS: Overall, these results validate the potential of T cell-based glioma therapy, even for glioma cells in hypoxic regions of the tumor. However, if sustained T cell responses are required for clinical efficacy, local amplification of anti-glioma effector cells may be limited by oxygen availability in the microenvironment, with the risk of accumulation of the immunosuppressive cytokine IL-10. SECONDARY CATEGORY: n/a.

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