"Suffocated CD8 T Cells in the Hypoxic Tumor Microenvironment" by Lourdes Beatriz Plaza Rojas

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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