Abstract 1369: Chronic stress drives ovarian cancer progression via MDSC infiltration and notch signaling pathway activation

Abstract Ovarian cancer (OC) is the fifth leading cause of cancer-related deaths among women in the U.S. Studies indicate that cancer patients have elevated stress hormones due to various stressors, which can disrupt cancer progression and immune response in the tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSC) are immature, immunosuppressive cells that play a crucial role in the TME and are associated with poor prognoses in cancer patients by disrupting several pathways, including the Notch signaling pathway (NSP). In various cancers, NSP dysregulation contributes to cancer progression. Increasing evidence suggests that chronic stress enhances MDSC infiltration, which promotes immunosuppression in the TME. However, the role of the NSP in stress-mediated MDSC infiltration and OC progression remains poorly understood. This study investigates how chronic stress affects NSP and MDSC biology in the OC TME and its role in disease progression. We hypothesize that chronic stress increases MDSC infiltration in the OC TME, enhancing NSP activity in OC cells. To test this, we inoculated female C57BL/6 mice with ID8Luc or IG10Luc OC cells and subjected them to daily restraint stress. Mice were sacrificed weekly for tumor and bone marrow collection, followed by immunofluorescence and flow cytometry analyses to characterize MDSC based on surface markers. We also isolated bone marrow from naïve C57BL/6 mice to differentiate myeloid cell precursors into MDSC. These cells were then exposed to stress hormones (norepinephrine (NE), epinephrine (EPI), and corticosterone (CC)) for 72 hours to analyze MDSC populations. Our results indicated that chronic restraint stress increased MDSC infiltration and enriched polymorphonuclear-MDSC (PMN-MDSC) in the TME and bone marrow of both OC mouse models. Results from the ex vivo experiments showed increased PMN-MDSC enrichment alongside a depletion of monocytic-MDSC in the groups treated with stress hormones. To further investigate the impact of stress hormones on NSP dysregulation, we treated OC cells (ID8 and IG10) in vitro with NE, EPI, or CC. Our findings revealed that stress hormones significantly upregulated the expression of the Notch Intracellular Domain (NICD) in OC cells. We also observed increased levels of Notch1, Jagged2, and Hes1 mRNA and protein, which may be mediated by GSK-3 phosphorylation. Additionally, we analyzed the expression of NSP members in tumors from the in vivo experiments. The results indicated higher expression levels of Notch1, Jagged2, NICD, and HES1 in tumors from mice subjected to restraint stress. These data suggest that chronic stress may induce MDSC infiltration and activity, possibly mediated by the activation of the NSP, thereby contributing to the immunosuppressive TME and progression of OC. Citation Format: Yadiel Alejandro Rivera-Lopez, Luinet L. Melendez-Rodriguez, Jaydiel A. Casiano-Martinez, Alanis P. Torres-Rosado, Sofia M. Hernandez-Carrasquillo, Melanie Ortiz-Leon, Luis M. Rivera-Perez, Zuliann S. Galarza-Ruiz, Orlando I. Torres-Rodriguez, Guillermo N. Armaiz-Pena. Chronic stress drives ovarian cancer progression via MDSC infiltration and notch signaling pathway activation [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 1369.