OR29-06 Liver Receptor Homolog 1 (LRH-1) regulates myeloid immune cell functions, revealing a new approach to cancer therapy

Abstract Disclosure: Y. Wang: None. N.A. Kulkarni: None. B. Duong: None. N. Krawczynska: None. S.V. Bendre: None. C.P. Schane: None. E. Weisser: None. L. Kockaya: None. Y. Fei: None. A. Das Gupta: None. H. Vidana Gamage: None. A.T. Nelson: None. S. He: None. S.G. Nanjappa: None. B.R. Gauthier: None. E.R. Nelson: None. Normal 0 false false false EN-US ZH-CN X-NONE /* Style Definitions */ table. MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Aptos",sans-serif; mso-ascii-font-family:Aptos; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Aptos; mso-hansi-theme-font:minor-latin; mso-fareast-language:ZH-CN;} Patients with high grade serous ovarian cancer or metastatic breast cancer have very poor 5-year survival rates. Furthermore, current standard of care therapies are often associated with significant side effects, including compromised immune systems. Thus, there is urgent need for new approaches to treating these diseases. Interestingly, we and others have implicated cholesterol in both of these cancers; elevated cholesterol being associated with poor prognosis, while patients on statins having an increased time to recurrence. Our previous work has identified myeloid immune cells as being very susceptible to perturbations in cholesterol homeostasis. The Liver Receptor Homolog 1 (LRH-1) is involved in regulating cholesterol catabolism. LRH-1 is expressed in myeloid immune cells, with relatively high expression in neutrophils. Neutrophils have been reported to have both pro- and anti-cancer functions. Therefore, we tested the hypothesis that LRH-1 regulates neutrophil functions important for cancer progression. We examined how LRH-1 activity influences various activities important for neutrophil function: migration, NETosis, phagocytosis and support of T cell activity. Adopting a pharmacologic approach, we found that LRH-1 decreased neutrophil migration toward cancer cells. LRH-1 was found to inhibit NETosis, a process where neutrophils extrude their DNA and associated proteins to form extracellular traps (NETs). LRH-1 activity in neutrophils also enhanced T cell expansion. Using murine models of mammary and ovarian cancer, we found that LRH-1 agonists reduced tumor growth, while an inverse agonist promoted tumor growth. NETosis has been described as a major driver of reemergence from breast cancer dormancy. Treatment of mice bearing dormant mammary cancer lesions with an LRH-1 inverse agonist significantly reduced the time to recurrence. Importantly, an agonist prolonged the time to recurrence. Thus, LRH-1 in neutrophils represents a novel target for the treatment of breast and ovarian cancer. Funding: National Cancer Institute (R01CA234025, R01CA288207, T32EB019944, T32GM136629, T32ES007326), Department of Defense (BCRP Era of Hope Award) Presentation: Monday, July 14, 2025