Date of Award

12-16-2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Charlie Garnett-Benson

Second Advisor

Yuan Liu

Third Advisor

Zhi-Ren Liu

Abstract

Radiotherapy remains effective at treating primary, early-stage tumors, however it produces nominal results in late-stage and metastatic tumors. This has led to a shift towards more targeted immune-based therapies. Yet the use of most approved cancer immunotherapies is limited to only a few cancer types and in the absence of effective anti-tumor immunity tumors can successfully evade immune surveillance. Tumors employ multiple mechanisms for avoiding immune elimination including down-regulation of positive signals to tumor specific CD8+ cytotoxic T cells (CTLs) and the accumulation of CD4+ regulatory T (TREG) cells which can suppress the anti-tumor activity of effector CTLs. Radiation has been reported to enhance anti-tumor immunity through such mechanisms as tumor cell death or phenotypic modulation of tumor cells, however the impact of radiotherapy on TREGcells is less clear.

The goal of this dissertation was to investigate the direct effect of radiation on the phenotypic characteristics and functional activity of induced TREGcells and to examine the indirect effect of radiation on TREGfrequency. We found that exposure to sub-lethal radiation decreased the expression of Foxp3 in TREGcells and differentially modulated the expression of several TREGsignature molecules. This loss of Foxp3 and modulation of several TREGassociated molecules resulted in a reduction of suppressive activity. Radiation has previously been shown to modulate the expression of genes in tumor cells that can impact T cell activity such as OX40L and 4-1BBL. Thus, a secondary goal of the research was to assess the effect of radiation-induced expression of tumoral OX40L and 4-1BBL on TREGnumber in two commonly used tumor models, 4T1 and MC38. Additionally, we examined 4T1 and MC38 tumors for changes in immune cell composition post-treatment. We found that radiation differentially modulated OX40L and 4-1BBL expression in our tumor models, as well as reduced TREGfrequency. However, induced expression of OX40L did not correlate with the observed decrease in TREGfrequency. Further, we found that radiotherapy differentially modulated the immune cell profile of 4T1 and MC38 tumors. These findings could support the design for rationale combinations of cancer immunotherapies with radiation treatment.

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