Abstract C027: The role of Liver Receptor Homolog 1 (LRH-1) in regulating cancer progression by modulating the immune response
Authors: Yu Wang, Bryan Duong, Natalia Krawczynska, Shruti V. Bendre, Claire P. Schane, Erin Weisser, Lara Kockaya, Yifan Fei, Anasuya Das Gupta, Hashni E. Vidana Gamage, Adam T. Nelczyk, Dhanya Pradeep, Erik R. Nelson
Journal: Cancer Research (2024)

Abstract Breast cancer is a significant global health concern, being the second most common type of cancer and the second leading cause of cancer-related deaths among women in the U.S. Metastatic breast cancer is responsible for most of these deaths, and current FDA-approved immunotherapies are effective only for a small subset of patients with PD-L1-positive tumors. Thus, there is a critical need for new therapeutic targets to enhance the immune response against breast cancer. Elevated plasma cholesterol concentrations are associated with poor breast cancer outcomes. Our previous studies indicated that myeloid immune cells are highly sensitive to changes in cholesterol levels and other proteins involved in regulating cholesterol homeostasis. However, the role of Liver Receptor Homolog 1 (LRH-1), a key regulator of cholesterol homeostasis, in myeloid cells is not well understood. Notably, higher expression of LRH-1 mRNA in breast tumors is associated with longer time to recurrence and improved overall survival. Therefore, we aimed to investigate the role of LRH-1 in myeloid immune cells and its impact on breast cancer progression. Initial analysis indicated that LRH-1 is expressed in myeloid cells, with particularly high levels observed in neutrophils. Therefore, we examined how LRH-1 regulates neutrophil functions important to cancer biology, including migration, NETosis, and phagocytosis, as well as its influence through neutrophils on T cells. We found that LRH-1 inhibited neutrophil migration toward cancer cells. Since tumor infiltrating neutrophils are generally associated with poor prognosis, LRH-1 reducing neutrophil migration could indicate a decreased ability of these immune-suppressive cells to infiltrate tumors. Importantly, neutrophils treated with an LRH-1 agonist showed reduced NETosis, while antagonist led to increased NETosis. LRH-1 agonist treatment also significantly reduced neutrophil phagocytosis, whereas an antagonist had no notable effect. Furthermore, T cells exhibited increased expansion when co-cultured with neutrophils treated with an LRH-1 agonist, and reduced proliferation with neutrophils pretreated with an LRH-1 antagonist or inverse agonist, particularly in CD4+ helper T cells and later divisions. Since neutrophils were previously implicated in invoking recurrence from dormant lesions, we evaluated LRH-1 in this context. The treatment of mice harboring dormant D2.0R lesions with an LRH-1 inverse agonist resulted in sooner recurrence and metastatic outgrowth compared to vehicle treated mice. In summary, our findings suggest that LRH-1 plays a crucial role in regulating various neutrophil functions, including migration, NETosis, phagocytosis, and T cell expansion. The ultimate consequence of these regulations are control of dormant mammary cancer lesions. These results highlight LRH-1 as a potential therapeutic target for cancer treatment or prevention of metastatic recurrence. Funding: National Cancer Institute (ERN: R01CA234025) Department of Defense (ERN: BCRP Era of Hope Award) Citation Format: Yu Wang, Bryan Duong, Natalia Krawczynska, Shruti V. Bendre, Claire P. Schane, Erin Weisser, Lara Kockaya, Yifan Fei, Anasuya Das Gupta, Hashni E. Vidana Gamage, Adam T. Nelczyk, Dhanya Pradeep, Erik R. Nelson. The role of Liver Receptor Homolog 1 (LRH-1) in regulating cancer progression by modulating the immune response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C027.