Adrenergic signaling inhibition to enhance the immunogenicity of the ovarian tumor microenvironment prior to PD-1 checkpoint therapy

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PROJECT SUMMARY There is growing evidence that links chronic stress to ovarian cancer progression. Cancer diagnosis, chemotherapy, and other traumatic life events can lead to altered psychological states such as chronic stress. Specifically, chronic stress induces sustained activation of the sympathetic nervous system and modulates physiological responses across different systems, including the immune system. Chronic stress results in the release of stress hormones, norepinephrine, and epinephrine known to redistribute T-cells, suppress CD8+ T- cells, and lead to worse prognoses. Preliminary data from this study team suggests that ascites-derived CD4+ and CD8+ T-cells express a heterogeneous pattern of activation and inhibitory receptors. Additionally, the team’s data showed that epinephrine stimulation of ascites-derived T-cells from ovarian cancer patients decreased Granzyme B expression, suggesting a decrease in CD8+ T-cell function. Moreover, the team’s preliminary data showed that daily restraint stress significantly increased ovarian cancer growth in various mouse models of disease. Hence, this proposal aims to characterize how stress hormones lead to an immunosuppressed ovarian cancer microenvironment and how this immunosuppression may decrease anti-PD-1 treatment efficacy. The study team’s overall hypothesis is that stress hormones suppress anti-tumor T-cell responses; thus, blockade of adrenergic signaling by pharmacologic methods will enhance T-cell function and improve the efficacy of PD-1 checkpoint inhibition therapy in ovarian cancer. Specific Aim 1 will characterize the effects of adrenergic signaling on CD4+ and CD8+ T-cell expression changes of activation/exhaustion markers, tumor recognition, and killing capacity of CD8+ T-cells. Specific Aim 2 will determine the effect of daily restraint stress and propranolol on anti-PD-1 treatment efficacy and T-cell biology in syngeneic mouse models of ovarian cancer. The proposed experiments aim to provide a comprehensive approach to elucidate the role of adrenergic signaling on T-cell function, tumor mutational burden, and checkpoint inhibition therapy efficacy. Data resulting from this proposal will support targeting stress hormone-mediated pathways to improve responses to immunotherapy in ovarian cancer patients. This study's long-term goal is to provide insight on potential predictive biomarkers of ovarian cancer patients’ response to immunotherapies with efforts to prevent and treat the effect of chronic stress on patients while improving clinical responses to checkpoint inhibition therapy.