Objectives A cancer diagnosis increases stress hormones and leads to altered psychological states. Work from our team suggests that chronic stress promotes an increased inflammatory response. Preliminary 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 loss of effector T-cell response and increased exhaustion.
Methods We obtained ascites samples from 66 patients with HGSOC and measured cytokine levels using a comprehensive cytokine/chemokine magnetic bead panel. Metanephrine (an epinephrine metabolite) 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.
Results Showed a significant increase in inflammatory cytokines in chemo-resistant and recurrent tumors: Eotaxin (p≤0.002), IL-6 (p≤0.003), and IL-7 (p≤0.009). Metanephrine, was positively correlated with pro-tumoral and inflammatory cytokines: SCD40L (p=0.032), FGF-2 (p=0.033) and MIP1a (p=0.03). Ascites-derived CD8+ T-cells treated with epinephrine, showed a decreased co-expression CD38 and Granzyme B (p=0.004). These results suggest a role for stress hormones in T-cell activity suppression.
Conclusions Chemo-resistant and recurrent tumors were associated with increased pro-inflammatory cytokines. Similarly, high metanephrine levels correlated with higher pro-tumoral cytokines. Epinephrine stimulation decreased CD8+ T-cell function in ascites of HGSOC patients. These data suggest a role for stress in immunosuppression and may impact efficacy of therapies that aim to restore T-cell function.
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