Improving natural killer cell response to brain tumor stem cells by targeting the αv integrin and TGF-β pathway

Glioblastoma stem cells (GSCs) are sensitive to lysis by healthy allogeneic natural killer (NK) cells in vitro.

• GSCs exhibit resistance to standard therapies, contributing to the recurrence of glioblastoma multiforme (GBM).
• Mass cytometry and single-cell RNA sequencing show that NK cells in GBM tumors have an altered phenotype with impaired lytic function compared to NK cells from peripheral blood.
• Direct contact between GSCs and NK cells activates TGF-β via αv integrin, leading to immune evasion by GSCs.
• Combining allogeneic NK cells with inhibitors of integrin or TGF-β signaling, or using TGFBR2 gene-edited NK cells, prevents GSC-induced dysfunction of NK cells and inhibits tumor growth.
• The αv integrin/TGF-β axis may represent a therapeutic target for GBM treatment.

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