Evaluating the Effect of IL-27 to Enhance poly(I:C)- and TRAIL-Induced Cell Death of Prostate Cancer Cells

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Kourko, Olena
Keyword
poly(I:C) , prostate cancer , natural killer cells , interleukin-27 , TRAIL
Abstract
Patients with advanced stage cancer face poor prognoses and restricted treatment options that often fail to provide improvement in disease progression. To address this therapeutic stagnancy, immunotherapies are being researched as potential therapies, which aim to enhance immune functions to target and suppress tumour growth. For example, recombinant cytokines can be used to manipulate immune cell responses and functions. Previous studies have demonstrated anti-tumour effects of cytokine IL-27 on various cancers, including prostate cancer, the second most common cancer diagnosed in men worldwide. A role for IL-27 in enhancing cellular responses to agents such as TLR agonists and its ability to act on multiple immune cells also makes IL-27 an attractive target for potential therapy. Therefore, my thesis aimed to investigate mechanisms underlying IL-27-mediated enhancement of apoptosis-inducing agonists and ligands, poly(I:C) and TRAIL, respectively. Using in vitro models of advanced prostate cancer, human PC3 and DU145 cell lines, I have investigated how IL-27 alters TLR3 expression and resulting enhanced poly(I:C)-mediated cell death. I found that this increase in cell death was dependent on secretion of IFN-beta from the prostate cancer cells. Secretion of IFN-beta in response to IL-27 and poly(I:C) also activated NK cells to target PC3 and DU145, which are resistant to NK cell cytotoxicity, for killing. I further characterized that the NK cells used TRAIL to induce death in the prostate cancer cells. This finding prompted further investigation into the differences in sensitivity of PC3 and DU145 cells to TRAIL-induced apoptosis. In comparison to DU145 cells, PC3 cells were more sensitive to TRAIL-induced apoptosis when stimulated with IL-27. The differential responses that I observed between the two prostate cancer cell types may be due to overall differences in the expression of IL-27 receptor and downstream signalling, as measured by STAT1 and STAT3 phosphorylation. The work conducted in this thesis provides a foundation for exploring IL-27 as an adjuvant to immunotherapies, while highlighting the importance of further advancing these results to determine suitable uses for this cytokine.
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