Glioblastoma (GBM) is the most aggressive form of primary brain tumor, characterized by immune evasion, rapid growth, extensive angiogenesis and peritumoral invasion into the brain parenchyma. Recent evidence indicates that epidermal growth factor-like protein 7 (EGFL7), a non-canonical regulator of NOTCH signalling and known angiogenic factor, is highly expressed in GBM microenvironment (GME).
We have observed that EGFL7 alters immune cells infiltrating the tumor mass, but the molecular mechanism remains elusive in GBM. Thus, in vivo studies in GBM mouse models followed by flow cytometry, single cell RNA-sequencing (scRNA-seq) and mass spectrometry were employed to uncover the type of cells and molecular mechanism by which EGFL7 regulates immune evasion. Our findings demonstrate that EGFL7 expression is detrimental for survival of glioma bearing mice while its elimination prolongs survival. We further identified specific immunosuppressive pro-tumorigenic immune cells: namely, regulatory T cells and myeloid-derived suppressor cells (MDSCs), showing a greater infiltration into the GME, in the presence of EGFL7. Concurrently, a reduction in cytotoxic T cells was observed. Using co-immunoprecipitation, we uncovered an interaction between EGFL7 and integrin β2 (present on immune cells). Further, scRNA-seq results provide a deeper understanding into the effect of EGFL7 on immune cell signaling. We believe this interaction is potentially responsible for inducing an immunosuppressive environment and places EGFL7 and integrin β2 at the center of glioma immunotherapy.
In conclusion, EGFL7 protein induces an immunosuppressive environment, possibly through its interaction with integrin β2 and this serves as a key step in developing treatment regimens against GBM.