EGFL7 promotes immune evasion in glioma through its interaction with integrin β2
Glioblastoma is the most aggressive form of malignant brain cancer, characterized by an immunosuppressive microenvironment and immune evasion. Despite the success of immune checkpoint inhibitors in other cancers, immunotherapies such as anti-PD1 have shown limited efficacy in glioblastoma, underscoring the need to identify tumor-intrinsic mechanisms that sustain this immunosuppressive microenvironment and to develop more effective therapeutic strategies targeting them. Previously, the secreted factor epidermal growth factor-like protein 7 (EGFL7) has been shown to promote brain tumor growth by affecting the glioblastoma microenvironment (GME). However, its impact on the immune system remained enigmatic. Here, we studied the role of EGFL7 in shaping the immune landscape in glioblastoma and identified the underlying molecular mechanisms it engages to drive glioma immune evasion. Single-cell transcriptomic profiling of immune cells derived of glioblastoma revealed that EGFL7 promotes an immunosuppressive GME, characterized by enhanced T cell exhaustion and polarization of macrophages towards a protumorigenic state. Proteomic profiling of EGFL7s interactome in glioma revealed its interaction with integrin {beta}2 (ITGB2), an immune cell surface receptor involved in cell adhesion and migration. Mechanistic studies uncovered the central role of this interaction for immune evasion, which promoted T cell exhaustion and the polarization of macrophages towards a pro-tumorigenic state. Genetic perturbation of the EGFL7-ITGB2 axis attenuated immunosuppression and prolonged the survival of glioblastoma-bearing mice. Remarkably, a combinatorial regimen of anti-EGFL7 and the checkpoint inhibitor anti-PD1 improved the efficacy of this drug, which by itself did not improve glioma patient survival so far. In conclusion, our study provides unequivocal evidence that EGFL7 mediates immune evasion in glioma and has great potential to serve as an add-on drug target to improve immunotherapies not functional in glioblastoma patients so far.