Date of Award
Doctor of Philosophy (PhD)
Microbiology, Molecular Biology and Biochemistry
Hypoxia is a common feature of solid tumors that plays an important role in angiogenesis, malignant progression and metastatic development. However, its impact on T cell anti-tumor responses is less known. We determined that CD8 tumor infiltrating lymphocytes (TILs) tend to localize to non-hypoxic tumor areas, suggesting a susceptibility to tumor-associated hypoxia. This led us to further study the effects of hypoxia in vitro by culturing spleen-derived mouse T cells in a humidified chamber at 0.5% O2, 5% CO2 and 37 °C. We found that T cell proliferation and effector function are reduced by hypoxia, severely affecting inflammatory cytokine production. While there was an increase in glucose use, as expected in healthy effector T cells, mitochondrial activity was reduced and lower ATP production was observed. Low cytokine production was also demonstrated in T cell receptor (TCR)-transduced human T cells, suggesting poor T cell function in hypoxic regions of the tumor in patients. Overall, we found that hypoxic T cell dysfunction is associated with defects in the TCR signaling and a metabolic shutdown of the cell under low O2 levels.
Plaza Rojas, Lourdes Beatriz, "Suffocated CD8 T Cells in the Hypoxic Tumor Microenvironment" (2020). Dissertations. 3815.
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Copyright © 2020 Lourdes Beatriz Plaza Rojas
Available for download on Wednesday, October 19, 2022