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.
