Abstract 1409: The role of liver receptor homolog 1LRH-1in regulating breast cancer progression by modulating the immune response

Abstract Breast cancer remains the second leading cause of cancer-related death among American women, with the majority of morality being associated with metastatic disease. At this stage, immunotherapy is only approved for a small subset of patients whose tumors are of the triple negative subtype TNBC that stain positive for PD-L1. However, the majority of these tumors prove refractory. Thus, it is imperative to develop novel therapeutic targets to improve the immune response in breast cancer. Since cholesterol metabolism is important for myeloid immune cell function, we launched studies to identify proteins involved in cholesterol homeostasis that are amenable to small molecule intervention. Liver Receptor Homolog 1 LRH-1/NR5A2 is highly expressed in myeloid cells, particularly neutrophils. We have found that elevated LRH-1 expression in breast cancer patients is associated with increased overall and recurrence-free survival rate. Thus, we hypothesized that LRH-1 acts as an immune modulator in myeloid cells, with subsequent effects on breast cancer progression. We initiated a series of experiments to characterize the role of LRH-1 in important aspects of neutrophil function: migration, NETosis, phagocytosis and influence on T cells. Neutrophils and neutrophil NETosis has previously been implicated in breast cancer progression including reemergence from dormancy and metastatic recurrence. Interestingly, we found that LRH-1 inhibits neutrophil migration towards cancer cells, a finding that may have important implications regarding infiltration of immune-suppressive myeloid cells. Furthermore, neutrophils treated with an LRH-1 agonist demonstrated decreased NETosis, while an antagonist resulted in increased NETosis. On the other hand, LRH-1 agonist treatment strongly decreased the neutrophil phagocytotic ability, while treatment with an antagonist did not significantly impact this process. Finally, T cells had increased expansion when cocultured with neutrophils that had been previously treated with an LRH-1 agonist, and reduced proliferation in the presence of neutrophils pretreated with an LRH-1 antagonist or inverse agonist. This was especially apparent in CD4+ helper T cells and later divisions. Ongoing work is aimed at determining the pathological relevance of these findings. Collectively, our data indicate that LRH-1 plays important roles in regulating different neutrophils functions, including migration, NETosis, phagocytosis, and T cell expansion. Overall, these findings suggest that LRH-1 in neutrophils regulates the immune response, and therefore can be a potential therapeutic target for cancer patients. 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, Erik R. Nelson. The role of liver receptor homolog 1LRH-1in regulating breast cancer progression by modulating the immune response abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1409.