BME Master’s Defense Announcement for Margaret E. Love (F. Huang and T. Ratliff, co-advisors)

Everyone is invited the attend the public presentation beginning at 3:00 PM.

Title: Linking Folate Receptor Beta Expression to Sex Differences and Metabolic Reprogramming in Tumor Associated Macrophages

Date: Tuesday, December 2, 2025

Time: 3:00 PM

Location: MJIS 2001

Committee: Dr. Fang Huang/Dr. Timothy Ratliff (co-advisors), Dr. Tamara Kinzer-Ursem

Abstract:

As tumors progress, their microenvironment is reshaped to support tumor growth, including the repolarization of tumor associated macrophages (TAMs) from tumor-killing to tumor-promoting states. One marker that identifies an immunosuppressive subset of TAMs, the folate receptor beta (FRβ), has become a promising target for immunotherapeutics because its expression correlates with poor overall survival and treatment resistance. The mechanisms governing upregulation of FRβ and its contribution to immunosuppressive activity remain poorly understood. In collaboration with Dr. Phillip Low’s group, we are testing a folate-conjugated TLR7 agonist (FA-TLR7a) designed to target FRβ⁺ TAMs and repolarize them toward an M1 phenotype. Treatment responses differ between males and females, motivating us to investigate sex-based differences in FRβ expression. We developed a FRβ-mCherry knock-in mouse model that allows for simple fluorescent identification of FRβ+ cells. Using dSTORM imaging, we observed higher FRβ expression in female monocytes, suggesting an explanation for these treatment disparities. To further define how FRβ contributes to macrophage function, I applied confocal and two-color expansion microscopy to visualize mitochondrial organization to study how the presence of folate metabolism (FOCM) influences mitochondrial function. Quantification of features such as network size, branch length, and footprint enabled mapping of macrophage polarization along the M1-to-M2 spectrum, where metabolism transitions from glycolysis to oxidative phosphorylation to support tumor-promoting functions. Findings indicate that FRβ expression correlates to a larger, more fused mitochondrial morphology, potentially indicating a more activated, polarized, and stabilized M2 phenotype to carry out suppressive function. I hypothesize this occurs through FOCM’s support of purine metabolism and stress response pathways, which enhance mtDNA generation and stability, reinforcing M2-like metabolism and promoting adenosine production. Bulk RNA sequencing of FRβ+ TAMs further supported this model, revealing upregulation of energy, purine metabolism, and antioxidants produced by FOCM. These analyses suggest that FOCM-driven purine metabolism and glutathione production by FOCM may increase adenosine levels and the differentiation of immunosuppressive prostaglandins. Overall, these findings point to a support system between FOCM and immunosuppressive function, but further analysis is needed to confirm the mechanisms at play.