Novel Strategies to Generate Tumor-Specific T Cells for Ovarian Cancer
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The highly immunosuppressive tumor microenvironment that characterizes ovarian cancer (OC) allows these tumors to grow undetected by the immune system, resulting in poor clinical outcomes for these patients with a five-year survival rate of just over 50%. This immune suppression can be partially reversed with the administration of epigenetic therapies, which induce type I and III interferon signaling in cancer cells by inducing the transcription of repetitive elements in the genome. While repetitive elements are epigenetically silenced in healthy cells, some of these elements can mobilize throughout the genome if not properly regulated. These elements with mobilization capabilities are termed transposable elements (TEs). As the transcribed conformations of many TEs resemble viral genomic material, the induced transcription of TEs by epigenetic inhibitors activates the innate immune response in cancer cells in a process termed “viral mimicry”. In addition to inducing viral mimicry, epigenetic therapy also upregulates the antigen processing and presentation machinery in tumor cells. As the number of intratumoral T cells in OC is positively correlated with increased survival rates in patients, this suggests that epigenetic therapy can be taken a step further by combining it with tumor-specific T cells. The overall aims of this work were to investigate whether TE-specific T cells could be generated to enhance the targeting and killing of OC cells. The presented work first reviews the mechanisms of epigenetic regulation of TEs in healthy cells and the consequences of their dysregulation and subsequent expression in cancer cells. Next, we describe the limited ability of T cells transduced with a T cell receptor recognizing a candidate epitope from the TE ERV-K-Env to target OC cell lines. We then show that TE-specific T cells cannot be expanded ex vivo using our established protocol with PBMCs from healthy donors or patients with cancer. Finally, we demonstrate the successful targeting of OC cell via ex vivo expanded polyclonal T cells generated using an antigen-agnostic method involving Prussian blue nanoparticles and photothermal therapy. Together, the work detailed in this dissertation describes novel efforts to expand tumor-specific T cells as a treatment for OC, with the eventual goal of combining them with epigenetic therapy to improve overall survival rates for patients with this malignancy.
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