APOE Drives Glioma Progression by Modulating CCL5/CCR5 Signaling in the Tumor Microenvironment and Inducing M2 Macrophage Polarization

Background

Tumor-associated macrophages (TAMs) are pivotal in shaping the tumor microenvironment (TME) during cancer progression. Emerging evidence indicates that dysregulation of key signaling pathways in cancer cells drives the secretion of various cytokines, modulating TAMs function. This study aimed to explore how glioblastoma cells regulate macrophages and establish a TME conducive to tumor immune escape.

Methods

In previous bioinformatics studies, we identified abnormally expressed genes in glioblastoma patients. Among them, the metabolism-related protein APOE garnered particular attention. We generated U87 and U251 cell lines with altered APOE expression to evaluate cancer cell invasion, migration, and inflammatory cytokine secretion through scratch assays, Transwell assays, and ELISA, respectively. Additionally, we established a co-culture system of cancer cells and monocytes THP-1 to assess the impact of shAPOE tumor cells on macrophage polarization using flow cytometry, Western blot, and immunofluorescence techniques.

Result

Knockdown of APOE significantly reduced the viability, invasion, and migration capabilities of U87 and U251 cells. ELISA results also showed that APOE knockdown cells secreted higher levels of IL-6, IL-12, and TNF-α, while CCL5 and TGF-β secretion was markedly reduced. In macrophage studies, we observed that APOE knockdown altered the M1/M2 polarization ratio in THP-1 monocytes, with CCR5 inhibition further decreasing M2 macrophage proportions. Immunofluorescence analysis revealed that the reduction of M2 macrophages was dependent on APOE and CCL5.

Conclusion

Our findings indicate that APOE knockdown suppresses glioblastoma cell migration, invasion, and CCL5 secretion, while enhancing the production of tumor-suppressive cytokines.