Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Science

Abstract

Adoptive cell transfer (ACT) immunotherapy using antigen (Ag)-specific T cells is partially effective treating several malignancies but numerous challenges remain in order to improve its therapeutic potential. The roles of host factors, such as sex hormone receptor signaling, that can affect the T cell anti-tumor function remain understudied. The work performed in this dissertation characterized the role of estrogen signaling on T cell function in vitro, and during ACT immunotherapy against hepatocellular carcinoma (HCC) in vivo. Estrogen signaling through ERa enhanced the expression and secretion of Type I effector cytokines including IFNg, TNFa, and Granzyme B in male and female Ag-specific T cells activated with their cognate Ag. Estrogen signaling through ERa enhanced the expression of the Type 2 cytokine IL-4 in male and female Ag-specific T cells. Estrogen signaling through ERb enhanced the polyfunctionality of male and female Ag-specific T cells activated with their cognate Ag. These results demonstrated for the first time that estrogen signaling through ERa and ERb can enhance the function of human Ag-specific T cells. Using an HCC mouse model treated with ACT immunotherapy, the effect of estrogen on the T cell anti-tumor immune response was measured. Estrogen presence resulted in reduced tumor burden and higher Ag-specific T cell tumor infiltration, survival, activation state, and cytokine expression. Removal of physiological estrogen reduced the survival and infiltration of CD4+ Ag-specific T cells. Lack of physiological estrogen during ACT also caused reduced cytokine production and polyfunctionality of CD4+ Ag-specific T cells. These results revealed for the first time that estrogen signaling can enhance the survival and function of CD4+ Ag-specific T cells in vivo which results in enhanced anti-tumor responses and reduced tumor burden. In summary, estrogen signaling enhances male and female Ag-specific T cell cytokine expression and secretion, and polyfunctionality which lead to enhanced tumor infiltration, survival, activation state, and function during ACT immunotherapy. This indicates that inducing estrogen signaling on Ag-specific T cells can enhance the efficacy and therapeutic outcome of ACT immunotherapy.

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

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