Abstract 2543: Chronic stress promotes tumor-associated inflammation in high-grade serous ovarian cancer
Authors: Aquino-Acevedo Alexandra N. , Knochenhauer Hope , Ortiz-León Melanie , Rivera-López Yadiel A. , Bonilla-Claudio Margarita , Yi John S. , Previs Rebecca A. , Armaiz-Pena Guillermo N. 
Published: June 2022

Abstract
A cancer diagnosis increases stress hormones levels and leads to altered psychological states. In the context of ovarian cancer (OC), chronic stress promotes tumor growth, chemoresistance and modulates immune cell populations in the tumor microenvironment (TME). Moreover, previous work from our team suggests that chronic stress promotes an increased inflammatory response in OC. Our data show an altered CD4+/CD8+ T-cell ratio and a heterogeneous expression of exhaustion markers in patients with high-grade serous ovarian cancer (HGSOC). Therefore, we hypothesized that chronic stress results in chronic inflammation and an immunosuppressed TME. To address this, we obtained ascites from 66 patients with HGSOC and measured cytokine levels using a comprehensive Cytokine/Chemokine immunoassay. Cortisol, corticosterone, and stress hormone metabolites (metanephrine and normetanephrine) levels from ascites were measured by ELISA. CD8+ T-cells isolated from OC patient ascites were stimulated with epinephrine, and flow cytometry was used to measure co-expression of CD38 activation marker and Granzyme B, an essential mediator of CD8+ T-cell killing capacity. To further establish the impact of chronic stress on tumor progression, we subjected IG10 or ID8 tumor-bearing C57/BL6 female mice to daily restraint stress. Mice were sacrificed 8-12 weeks after inoculation, data collected, and ascites stored. Results showed an increase in inflammatory cytokines (Eotaxin, IL-6, and IL-7) in recurrent tumors of HGSOC patients. IP-10 and IFN-γ were negatively associated with cortisol levels. Moreover, normetanephrine levels positively correlated with inflammatory cytokines: IL-6, MCP-1, MCP-3, VEGF, GRO, and IL-7. Metanephrine was also positively correlated with inflammatory cytokines: SCD40L, FGF-2, and MIP1α. Ascites-derived CD8+ T-cells treated with epinephrine showed decreased co-expression CD38 and Granzyme B. Additionally, data show that daily restraint stress led to increased tumor growth in ID8 and IG10 syngeneic mouse models of OC. Ascites derived from our animal models suggest a positive correlation of inflammatory cytokines VEGF, TNFα and Eotaxin, and corticosterone levels in ID8 tumor-bearing mice. These results suggest a role for stress hormones in inflammation and immunosuppression. In conclusion, inflammatory cytokines are upregulated in recurrent HGSOC ascites samples. Cytokines that regulate T-cell function were negatively associated with cortisol levels, while stress hormone metabolites correlated with higher inflammatory cytokines. Moreover, epinephrine stimulation decreased ascites-derived CD8+ T-cell function. Inflammatory cytokines correlated with corticosterone levels in ID8 tumor-bearing mice. Overall, these data suggest a role for chronic stress in inflammation and immunosuppression, impacting the efficacy of therapies that aim to restore T-cell function.
Citation Format: Alexandra N. Aquino-Acevedo, Hope Knochenhauer, Melanie Ortiz-León, Yadiel A. Rivera-López, Margarita Bonilla-Claudio, John S. Yi, Rebecca A. Previs, Guillermo N. Armaiz-Pena. Chronic stress promotes tumor-associated inflammation in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2543.