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

Plasma cholesterol is correlated with worse outcomes in breast and ovarian cancer. Prior work indicates that myeloid immune cells are highly responsive to cholesterol metabolism. Interestingly, Liver Receptor Homolog-1 (LRH-1, or NR5A2), a key transcriptional regulator of cholesterol homeostasis is highly expressed in neutrophils and is associated with increased survival time. However, the roles of LRH-1 within neutrophils remain unclear. We therefore focused on how LRH-1 influences neutrophil behaviors relevant to cancer. Small molecule ligands for LRH-1 regulated neutrophil migration towards cancer cells. Phagocytosis was also regulated by LRH-1 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. NETosis is a known trigger of recurrence from dormancy and subsequent tumor growth. Importantly LRH-1 activation reduced NETosis, while treatment with an antagonist or inverse agonist enhanced NETosis, likely through altered reactive oxygen species. Treatment of mice with an inverse agonist of LRH-1 increased the growth of mammary tumors in a NET-dependent manner. Mice harboring dormant D2.0R mammary cancer lesions treated with an LRH-1 inverse agonist exhibited earlier tumor recurrence and enhanced metastatic progression. In contrast, treatment with BL001, a small chemical LRH-1 agonist, delayed recurrence in D2.0R-grafted mice. These findings reveal that LRH-1 is a novel regulator of neutrophil-driven immune responses within the tumor microenvironment. LRH-1 is thus a promising therapeutic target to suppress the progression of breast and ovarian cancer.