Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells

• Published in: The Journal of clinical investigation Vol. 131; no. 14; pp. 1 - 15
• Main Authors: Shaim, Hila, Shanley, Mayra, Basar, Rafet, Daher, May, Gumin, Joy, Zamler, Daniel B., Uprety, Nadima, Wang, Fang, Huang, Yuefan, Gabrusiewicz, Konrad, Miao, Qi, Dou, Jinzhuang, Alsuliman, Abdullah, Kerbauy, Lucila N., Acharya, Sunil, Mohanty, Vakul, Mendt, Mayela, Li, Sufang, Lu, JunJun, Wei, Jun, Fowlkes, Natalie W., Gokdemir, Elif, Ensley, Emily L., Kaplan, Mecit, Kassab, Cynthia, Li, Li, Ozcan, Gonca, Banerjee, Pinaki P., Shen, Yifei, Gilbert, April L., Jones, Corry M., Bdiwi, Mustafa, Nunez-Cortes, Ana K., Liu, Enli, Yu, Jun, Imahashi, Nobuhiko, Muniz-Feliciano, Luis, Li, Ye, Hu, Jian, Draetta, Giulio, Marin, David, Yu, Dihua, Mielke, Stephan, Eyrich, Matthias, Champlin, Richard E., Chen, Ken, Lang, Frederick F., Shpall, Elizabeth J., Heimberger, Amy B., Rezvani, Katayoun
• Format: Journal Article
• Language: English
• Published: Ann Arbor American Society for Clinical Investigation 15.07.2021
• Subjects: Astrocytes; Biomedical research; Brain cancer; Cancer therapies; Cytometry; Cytotoxicity; Genotype & phenotype; Glioblastoma; Immunotherapy; Ligands; Lysis; Medicin och hälsovetenskap; Natural killer cells; Patients; Peripheral blood; Phenotypes; Stem cell transplantation; Stem cells; Therapeutic targets; Transforming growth factor-b; Tumors
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI142116

Glioblastoma multiforme (GBM), the most aggressive brain cancer, recurs because glioblastoma stem cells (GSCs) are resistant to all standard therapies. We showed that GSCs, but not normal astrocytes, 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 from patients with GBM or healthy donors. We attributed this immune evasion tactic to direct cell-to-cell contact between GSCs and NK cells via av integrin-mediated TGF-β activation. Treatment of GSC-engrafted mice with allogeneic NK cells in combination with inhibitors of integrin or TGF-β signaling or with TGFBR2 gene-edited allogeneic NK cells prevented GSC-induced NK cell dysfunction and tumor growth. These findings reveal an important mechanism of NK cell immune evasion by GSCs and suggest the av integrin/TGF-β axis as a potentially useful therapeutic target in GBM.