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

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Program Director/Principal Investigator (Last, First, Middle): Armaiz-Pena, Guillermo N. PROJECT SUMMARY Growing evidence suggests that altered psychological states, such as chronic stress, anxiety, and depression negatively impact patients with ovarian cancer. Multiple studies report that ovarian cancer patients suffer from increased psychological distress following their diagnosis and during treatment, which contributes to worsened quality of life and decreased overall survival. These altered psychological states have been linked to increased stress hormones levels, tumor-associated inflammation, and disease progression. Data supporting this proposal demonstrates how daily restraint stress leads to increased cytokine levels, macrophage infiltration and activity, and ovarian cancer progression in animal models. On the other hand, how adrenergic signaling affects anti- tumor immune responses remains poorly understood. This proposal demonstrates that ascites from ovarian cancer patients are highly immunosuppressed and T-cells isolated from ascites express an abundance of inhibitory markers; making this research extremely relevant as recent clinical trials targeting T cells in ovarian cancer have not been successful. Hence, the overall hypothesis states that stress hormones suppress anti-tumor T cell responses; thus, blockade by pharmacologic methods will enhance T cell function and improve the efficacy of checkpoint inhibition therapy in ovarian cancer. Specific Aim 1 will characterize the immunologic changes that adrenergic signaling has on cytokines and T cell responses in ovarian cancer patients. In Specific Aim 2, the study team will determine the impact of daily restraint stress on T cell function through pre-clinical models of ovarian cancer treated with anti-PD-1 therapy and propranolol. The study team is confident that this proposal will provide a comprehensive approach to dissect the role of chronic stress on cancer-associated immune processes, such as T cell function and checkpoint inhibition efficacy, that lead to disease progression. Results from this proposal will identify immune signatures of response and provide a rationale for interventions aimed at preventing and treating chronic stress experienced by ovarian cancer patients, with the ultimate goal of improving clinical responses to checkpoint blockade therapy. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page