Date of Award

2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology, Molecular Biology and Biochemistry

Abstract

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.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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