Abstract 4833: Targeting DOT1L to enhance the immune response in ovarian cancer

Abstract Epithelial ovarian cancer stands as the second most prevalent cause of death among all gynecological cancers. Current treatment protocols for patients incorporate platinum-based therapy regimens along with PARP inhibitors tailored for HR-deficient high-grade serous ovarian cancers (HGSOC). Despite initial efficacy, patients inevitably develop disease progression as tumor cells acquire resistance. HGSOC is characterized by low immune cell infiltration and reduced anti-tumor immune response. MHC class I mediated antigen presentation by cancer cells to the immune cells is one of the steps required to activate the anti-tumor immune response. Therefore, HGSOC often downregulates MHC class I expression to evade immune surveillance. To identify epigenetic factors negatively regulating MHC class I expression, we conducted a comparative analysis of HGSOC patient cell samples and HGSOC cell lines from the TCGA and DepMap. Our findings indicate that the epigenetic regulator DOT1L is overexpressed in ovarian cancer and negatively correlates with MHC class I expression. DOT1L is an enzyme responsible for the methylation of lysine79 on histone3 that regulates gene expression. However, the role of DOT1L in regulating MHC class I or antitumor immune response has not been previously studied. We hypothesized that DOT1L might regulate the expression of MHC class I in ovarian cancer and block the immune response. To investigate the role of DOT1L in the regulation of MHC class I, we generated a DOT1L knockout in two DOT1L-high EOC cell lines, OVCAR3 and ID8. Genetic inhibition of DOT1L led to enhanced expression of MHC class I on the surface of both cell lines. This suggests that DOT1L inhibition might be a valuable strategy to upregulate MHC class I expression, which could lead to an increased anti-tumor immune response. Importantly, a small-molecule DOT1L inhibitor, Pinometostat, is currently in late-stage clinical trials for other types of cancer. We then tested the effect of Pinometostat on MHC class I expression. In accordance with our hypothesis, DOT1L pharmacological inhibition also promoted upregulation of MHC class I expression in both cell lines. This discovery could potentially pave the way for the development of DOT1L inhibitors for HGSOC to increase anti-tumor immune response in ovarian cancer. The present research indicates that DOT1L inhibitors have the potential to be utilized in the precision medicine strategy for addressing DOT1L-high ovarian cancer patients. Citation Format: Aisha Jamil, Shraddha Gupta, Sangeeta Kumari, Deyana Tabatabaei, Sergey Karakashev. Targeting DOT1L to enhance the immune response in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4833.