LRH-1 is a novel regulator of neutrophil-driven immune responses within the tumor microenvironment

Elevated plasma Cholesterol levels have been linked to worse outcomes in breast and ovarian Cancer. Prior work including our own has demonstrated that myeloid immune cells are highly responsive to Cholesterol fluctuations and to proteins involved in Cholesterol regulation. However, the specific roles of Liver Receptor Homolog-1 (LRH-1, or NR5A2), a key transcriptional regulator of Cholesterol homeostasis, within myeloid cells remains largely undefined. Interestingly, LRH-1 mRNA levels are reduced in both breast and ovarian tumors compared to normal tissue. Its elevated expression within tumors is associated with increased survival time. These clinical correlations prompted us to explore the role of LRH-1 in myeloid cells particularly in the context of breast and ovarian Cancer progression. Initial analyses confirmed LRH-1 expression in various myeloid cell types, with particularly high levels in neutrophils. We therefore focused on how LRH-1 influences neutrophil behaviors relevant to Cancer, including migration, NETosis, phagocytosis, and interactions with T cells. Small molecule ligands for LRH-1 regulated neutrophil migration towards Cancer cells. Phagocytosis was also regulated by LRH-1 small molecule ligands, the extent being dependent on type of bait ( e. coli vs. Cancer cells). In T cell co-cultures, neutrophils pretreated with an LRH-1 agonist promoted greater T cell expansion - particularly in CD4⁺ cells - while LRH-1 inhibition suppressed this response. Moreover, LRH-1 activation reduced NETosis, while treatment with an antagonist or inverse agonist enhanced NETosis. Treatment of mice with an inverse agonist of LRH-1 increased the growth of 4T1 and E0771 mammary tumors. Given prior evidence that neutrophils contribute to the recurrence of dormant lesions, we further examined the role of LRH-1 in this context. Mice harboring dormant D2.0R mammary Cancer lesions treated with an LRH-1 inverse agonist exhibited earlier tumor recurrence and enhanced metastatic progression compared to vehicle-treated controls. In contrast, treatment with BL001, a small chemical LRH-1 agonist, delayed recurrence in D2.0R-grafted mice. Collectively, these findings reveal that LRH-1 is a novel regulator of neutrophil-driven immune responses within the tumor microenvironment. LRH-1 thus remerges as a promising therapeutic target to suppress metastasis or prevent recurrence in breast Cancer.