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Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells
Hila Shaim, … , Amy B. Heimberger, Katayoun Rezvani
Hila Shaim, … , Amy B. Heimberger, Katayoun Rezvani
Published June 17, 2021
Citation Information: J Clin Invest. 2021;131(14):e142116. https://doi.org/10.1172/JCI142116.
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Research Article Immunology Article has an altmetric score of 139

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

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Abstract

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 αv 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 αv integrin/TGF-β axis as a potentially useful therapeutic target in GBM.

Authors

Hila Shaim, Mayra Shanley, Rafet Basar, May Daher, Joy Gumin, Daniel B. Zamler, Nadima Uprety, Fang Wang, Yuefan Huang, Konrad Gabrusiewicz, Qi Miao, Jinzhuang Dou, Abdullah Alsuliman, Lucila N. Kerbauy, Sunil Acharya, Vakul Mohanty, Mayela Mendt, Sufang Li, JunJun Lu, Jun Wei, Natalie W. Fowlkes, Elif Gokdemir, Emily L. Ensley, Mecit Kaplan, Cynthia Kassab, Li Li, Gonca Ozcan, Pinaki P. Banerjee, Yifei Shen, April L. Gilbert, Corry M. Jones, Mustafa Bdiwi, Ana K. Nunez-Cortes, Enli Liu, Jun Yu, Nobuhiko Imahashi, Luis Muniz-Feliciano, Ye Li, Jian Hu, Giulio Draetta, David Marin, Dihua Yu, Stephan Mielke, Matthias Eyrich, Richard E. Champlin, Ken Chen, Frederick F. Lang, Elizabeth J. Shpall, Amy B. Heimberger, Katayoun Rezvani

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Figure 5

In vivo antitumor activity and NK cell function following TGF-β and αv integrin signaling inhibition in a GBM mouse model.

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In vivo antitumor activity and NK cell function following TGF-β and αv i...
(A) Schematic diagram showing the timeline of the in vivo experiment. (B) Bioluminescence imaging (BLI) at different time points was used as a surrogate marker for tumor progression (n = 4–5). (C) Average radiance (BLI) data. Orange asterisks: NK + galunisertib vs. tumor control. Red asterisks: NK + cilengitide vs. tumor control. Blue asterisks: NK alone vs. tumor control. Green asterisks: NK + galunisertib vs. cilengitide control. Brown asterisks: NK + cilengitide vs. cilengitide control. Purple asterisks: NK + galunisertib vs. galunisertib control. (D) Survival of mice in each group (n = 5). Animals treated with NK + galunisertib or NK + cilengitide had significantly better survival compared with tumor controls (P = 0.009 and P = 0.05, respectively). (E and F) viSNE plots (E) and comparative heatmap (F) of mass cytometry data showing the expression of NK cell markers in WT or TGFBR2-KO NK cells with or without recombinant TGF-β. Heatmap column clustering generated by FlowSOM analysis; color scale shows the expression of each marker: red (high) and blue (low). (G) Killing of K562 cells over time by WT-NK (blue), TGFBR2-KO NK (black), WT-NK + recombinant TGF-β (red), or TGFBR2-KO NK + recombinant TGF-β (green) as measured by real-time killing assay. (H) Schematic diagram showing the timeline of subsequent in vivo mouse experiment. (I) BLI was obtained from the 4 groups of mice (n = 4). (J) Average radiance (BLI) data: Red asterisks: TGFBR2-KO NK vs. tumor controls. Green asterisks: WT NK + galunisertib vs. tumor controls. Blue asterisks: WT NK vs. tumor controls. (K) Kaplan-Meier plot showing mouse survival. Statistical analysis by 2-way ANOVA with Dunnett’s correction for multiple comparisons (C, G, and J) or log-rank test (D and K). *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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