The αv integrins mediate NK cells immune evasion in GBM through the modulation of the TGF-β axis

Glioblastoma, the most aggressive brain cancer, invariably recurs with current standard therapies. I showed that glioblastoma cells are sensitive to lysis by healthy allogeneic natural killer (NK) cells in vitro. Mass cytometry and single-cell RNA sequencing of primary tumor samples revealed that GBM tumor-infiltrating NK cells acquired an altered phenotype associated with impaired lytic function relative to matched peripheral blood NK cells. I attributed this immune evasion tactic to direct cell-to-cell contact between GSCs and NK cells via αv integrin-mediated TGF-β activation. Treatment of glioblastoma-engrafted mice with allogeneic NK cells in combination with inhibitors of integrin or TGF-β signaling or with TGFBR2 Knockout NK cells prevented glioblastoma induced NK cell dysfunction and tumor growth. These findings reveal an important mechanism of NK cell immune evasion by glioblastoma and reveals the αv integrin/TGF-β axis as an important therapeutic target in glioblastoma.