DESCRIPTION (provided by applicant): The laying hen is an emerging animal model of spontaneous ovarian cancer (OVCA). This model addresses a gap between studies of spontaneous human OVCA and non-spontaneous, engineered models of OVCA. Evidence suggests the hen can provide needed information on early events related to the role of inflammation and autoimmunity in the etiology of OVCA since humans and hens have striking similarities in ovarian physiology, anti-ovarian autoantibodies (AOA), anti-tumor antibodies and OVCA and immune cell trafficking into tumors. Interestingly, ovarian autoimmunity and AOA are associated similarly with prematurely decreased ovarian function in middle aged women and hens. We showed that both hen and human OVCA are associated with AOA and with antibodies to the same tumor antigens (e.g., mesothelin (MSLN), Selenium Binding Protein 1 (SBP1) and p53. In a pilot study, hens with normal ovaries but low egg laying (i.e., reduced ovarian function)
with AOA developed OVCA within 10 months suggesting that autoimmunity could precede or predict OVCA. The concept that autoimmunity is linked to cancer is not new. However, the potential progression of autoimmunity to OVCA has been minimally explored given the logistics of carrying out such studies in humans. The relationship among autoantibodies, inflammation and spontaneous tumor development can easily be tested in hens. In this study we will use the laying hen model of OVCA to determine (Aim 1) whether serum autoantibodies to specific antigens such as anti-mesothelin (MSLN), anti-p53 and/or anti-selenium binding protein 1 (SBP1) predict OVCA, if antibodies are correlated with increased lymphocyte numbers in the ovary and if these changes in immunity are more often associated with a pro-inflammatory environment in the ovary, and (Aim 2) confirm that FTY720 (fingolimod; an S1P agonist that is FDA approved for amelioration of the autoimmune disease, multiple sclerosis) reverses lymphocyte infiltration and inflammation and improves ovarian function and that this is associated with a decrease in a surrogate endpoint (angiogenesis) for OVCA incidence. Accomplishment of these Aims will provide further evidence for antibodies as markers for OVCA and for reduction of OVCA by an immunosuppressant. This will contribute to knowledge of a mechanism involved in OVCA generation that can be targeted to prevent or control OVCA.