TY - JOUR
T1 - Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells
AU - Shaim, Hila
AU - Shanley, Mayra
AU - Basar, Rafet
AU - Daher, May
AU - Gumin, Joy
AU - Zamler, Daniel B.
AU - Uprety, Nadima
AU - Wang, Fang
AU - Huang, Yuefan
AU - Gabrusiewicz, Konrad Ryszard
AU - Miao, Qi
AU - Dou, Jinzhuang
AU - Alsuliman, Abdullah
AU - Kerbauy, Lucila Nassif
AU - Acharya, Sunil
AU - Mohanty, Vakul
AU - Mendt Vilchez, Mayela Carolina
AU - Li, Sufang
AU - Lu, Jun Jun
AU - Wei, Jun
AU - Fowlkes, Natalie W.
AU - Gokdemir, Elif
AU - Ensley, Emily L.
AU - Kaplan, Mecit
AU - Kassab, Cynthia
AU - Li, Li
AU - Ozcan, Gonca
AU - Banerjee, Pinaki P.
AU - Shen, Yifei
AU - Gilbert, April L.
AU - Jones, Corry M.
AU - Bdiwi, Mustafa
AU - Nunez-Cortes, Ana K.
AU - Liu, Enli
AU - Yu, Jun
AU - Imahashi, Nobuhiko
AU - Muniz-Feliciano, Luis
AU - Li, Ye
AU - Hu, Jian
AU - Draetta, Giulio
AU - Marin, David
AU - Yu, Dihua
AU - Mielke, Stephan
AU - Eyrich, Matthias
AU - Champlin, Richard E.
AU - Chen, Ken
AU - Lang, Frederick F.
AU - Shpall, Elizabeth J.
AU - Heimberger, Amy B
AU - Rezvani, Katayoun
N1 - Publisher Copyright:
© 2021, American Society for Clinical Investigation.
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI142116
DO - 10.1172/JCI142116
M3 - Article
C2 - 34138753
AN - SCOPUS:85109072960
SN - 0021-9738
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 14
M1 - e142116
ER -