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

被引：166

作者：

Shaim, Hila ^{[1
,2
]}

Shanley, Mayra ^{[1
]}

Basar, Rafet ^{[1
]}

Daher, May ^{[1
]}

Gumin, Joy ^{[3
]}

Zamler, Daniel B. ^{[4
]}

Uprety, Nadima ^{[1
]}

Wang, Fang ^{[5
]}

Huang, Yuefan ^{[5
]}

Gabrusiewicz, Konrad ^{[3
]}

Miao, Qi ^{[5
]}

Dou, Jinzhuang ^{[5
]}

Alsuliman, Abdullah ^{[1
]}

Kerbauy, Lucila N. ^{[1
]}

Acharya, Sunil ^{[1
]}

Mohanty, Vakul ^{[5
]}

Mendt, Mayela ^{[1
]}

Li, Sufang ^{[1
]}

Lu, JunJun ^{[1
]}

Wei, Jun ^{[3
]}

Fowlkes, Natalie W. ^{[6
]}

Gokdemir, Elif ^{[1
]}

Ensley, Emily L. ^{[1
]}

Kaplan, Mecit ^{[1
]}

Kassab, Cynthia ^{[3
]}

Li, Li ^{[1
]}

Ozcan, Gonca ^{[1
]}

Banerjee, Pinaki P. ^{[1
]}

Shen, Yifei ^{[5
]}

Gilbert, April L. ^{[1
]}

Jones, Corry M. ^{[1
]}

Bdiwi, Mustafa ^{[1
]}

Nunez-Cortes, Ana K. ^{[1
]}

Liu, Enli ^{[1
]}

Yu, Jun ^{[3
]}

Imahashi, Nobuhiko ^{[1
]}

Muniz-Feliciano, Luis ^{[1
]}

Li, Ye ^{[1
]}

Hu, Jian ^{[7
]}

Draetta, Giulio ^{[4
]}

Marin, David ^{[1
]}

Yu, Dihua ^{[8
]}

Mielke, Stephan ^{[2
,9
]}

Eyrich, Matthias ^{[10
]}

Champlin, Richard E. ^{[1
]}

Chen, Ken ^{[5
]}

Lang, Frederick F. ^{[3
]}

Shpall, Elizabeth J. ^{[1
]}

Heimberger, Amy B. ^{[3
]}

Rezvani, Katayoun ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA

[2] Univ Med Ctr Wurzburg, Dept Internal Med 2, Wurzburg, Germany

[3] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Vet Med & Surg, Houston, TX USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX USA

[9] Karolinska Inst, Dept Hematol, Stockholm, Sweden

[10] Univ Med Ctr Wurzburg, Dept Pediat Hematol Oncol & Stem Cell Transplanta, Wurzburg, Germany

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2021年 / 131卷 / 14期

关键词：

GROWTH-FACTOR-BETA; MATRIX METALLOPROTEINASES; ALPHA-V-BETA-6; INTEGRIN; IMMUNE INFILTRATION; BRAIN-TUMOR; GALUNISERTIB; MICROENVIRONMENT; ACTIVATION; INHIBITOR; LOMUSTINE;

D O I：

10.1172/JCI142116

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 cellto-cell contact between GSCs and NK cells via alpha v integrin-mediated TGF-beta activation. Treatment of GSC-engrafted mice with allogeneic NK cells in combination with inhibitors of integrin or TGF-beta 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 alpha v integrin/TGF-beta axis as a potentially useful therapeutic target in GBM.

引用

页数：16

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