The Role of TP53, ADAR1, and T Cells in the Interferon Response to DNMTi Therapy in Ovarian Cancer Model
Open Access DepositedIn recent decades, significant advances in cancer research have led to the development of many novel therapies that have found great success in the clinic. However, the death rate of ovarian cancer (OC) has remained stagnant, and the five-year survival rate is only 50.8%. The tumor microenvironment (TME) and mutational burden are two significant challenges in treating OC. More than 96% of OC exhibit mutations in the tumor suppressor gene TP53. The DNA methyltransferase inhibitors (DNMTis) 5-Azacytidine (Aza) and 5-Aza-2ʹ-Deoxycytidine (Dac) activate interferon (IFN) signaling in tumor cells. Knockdown of adenosine deaminase 1 (ADAR1/Adar1), an enzyme that inhibits the IFN response, in combination with DNMTi treatment, significantly increases survival in a murine model of OC. In this thesis, human ADAR1 knockdown (KD) OC cell lines with different TP53 mutation status were treated with Aza, Dac, and a novel DNMTi, GSK3685032 (GSK), in vitro to investigate the effect. IFN response was measured by the secretion of IFN-? and increased interferon-stimulated genes (ISGs) transcription. Wildtype (WT) TP53 OC cell lines had IFN responses to both control and ADAR1 KD. Mutant cell lines had a more significant response in the ADAR1 KD condition than the control. In the null cell lines, the cells did not have a robust IFN response in either the control or ADAR1 KD. To further investigate the effect of DNMTis in the IFN response, primary murine T cells were treated with the same DNMTis. IFN-? secretion and ISG transcription increased with all DNMTi treatments. This study demonstrates that DNMTi therapy activates immune cells in vitro. The study also provides insight into the role of TP53 in OC’s response to DNMTi therapy.
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