Abstract 6120: The effect of chronic stress in T-cell population and function in ovarian cancer
Authors: Morales-López Camily , Aquino-Acevedo Alexandra , Cruz-Robles Melanie E. , Ortiz-León Melanie , Hernández-Cordero Elvin R. , Rivera-López Yadiel A. , Rivera-Bonilla Margarita , Previs Rebecca A. , Armaiz-Pena Guillermo N. 
Published: June 2022

Abstract
Ovarian cancer (OC) is the deadliest form of gynecological malignancies highlighted by a five-year survival rate of less than 49%. Late diagnosis and chemoresistance represent the main hurdle in the effort to improve OC patient outcomes. Currently, immunotherapy is studied as an alternative to front-line therapy, but its use in the clinic remains limited due to its modest impact on patient outcomes. It is well known that the neuroendocrine system can modulate immune cell behavior. This study aims to determine how behavioral factors, such as chronic stress and an associated increase in stress hormone levels, impact T-cell infiltration and function in ovarian cancer. As T-cells play a central role in cancer recognition and killing, we hypothesize that stress hormones could decrease the efficacy of checkpoint blockade by inducing changes in T-cell populations and contribute to T-cell exhaustion (determined by the expression of PD-1, TIM-3, FOXP3, and CTLA-4). We obtained tumor samples from C57/BL6 ID8 tumor-bearing mice subjected to daily restraint stress to dissect the interaction between the neuroendocrine system and tumor-associated T-cells. Unstressed mice were used as controls. Tumors from both groups were collected and preserved with paraffin for histological assessments. Immunohistochemistry analyses were used to evaluate the presence of CD4+ and CD8+ T-cells. To measure specific CD4+ T-cell subtype, regulatory T-cells (T-reg), FOXP3 was used as a marker. In addition, we assessed for T-cell surface markers PD-1, CTLA-4, and TIM-3. Results show a significant increase in PD1+ expressing cells (2.35x-fold; p= 0.0173) in tumors from the stress group. On the other hand, there was a non-significant decrease in CD4+ T-cells (0.78x-fold; p=0.4286) and non-significant increase in CD8+ T-cells (1.75x-fold; p= 0.1833) between groups. Although we did not observe significant differences in FOX-P3 (1.4x-fold; p=0.3152), we did observe a trend towards increased expression of this transcription factor, suggesting a predominance of T-regs in the tumor microenvironment. When comparing the presence of surface markers, there was a non-significant increase in TIM-3 (1.56x-fold; p=0.5273) and CTLA-4 (1.32x-fold; p=0.5303) positive cells in the tumor microenvironment of samples from the stress group. These data suggest that the neuroendocrine system may modulate T-cell activity, specifically the expression of PD-1 ligand. Furthermore, sustained release of stress hormones may promote an immunosuppressive tumor microenvironment, leading to T-cell exhaustion, immune evasion, and tumor progression.
Citation Format: Camily Morales-López, Alexandra Aquino-Acevedo, Melanie E. Cruz-Robles, Melanie Ortiz-León, Elvin R. Hernández-Cordero, Yadiel A. Rivera-López, Margarita Rivera-Bonilla, Rebecca A. Previs, Guillermo N. Armaiz-Pena. The effect of chronic stress in T-cell population and function in 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 6120.