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

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; Jun Jun 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

doi:10.1172/JCI142116

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

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, Jun Jun Lu, Jun WeiNatalie 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^*

^*Corresponding author for this work

Neurological Surgery

Research output: Contribution to journal › Article › peer-review

129 Scopus citations

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.

Original language	English (US)
Article number	e142116
Journal	Journal of Clinical Investigation
Volume	131
Issue number	14
DOIs	https://doi.org/10.1172/JCI142116
State	Published - Jul 2021

Funding

This research was generously supported in part by Ann and Clarence Cazalot, the Dr. Marnie Rose Foundation, and the University of Texas MD Anderson Cancer Center Glioblastoma Moonshot Program. This work was funded by grants from the NIH (CA120813), the Specialized Program of Research Excellence (SPORE) in Brain Cancer grant (P50CA127001), and the NCI Cancer Center Support Grant (P30CA16672), which also supports the MD Anderson Flow Cytometry and Cellular Imaging Core Facility (FCCICF) that assisted with the CyTOF studies in this project. We thank our summer students Nadia Agha (University of Houston), Cindy Saliba (University of Iowa), and Lihi Shalev (Hebrew University of Jerusalem) for their assistance with some of the experiments performed in the study.

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1172/JCI142116

Cite this

Shaim, H., Shanley, M., Basar, R., Daher, M., Gumin, J., Zamler, D. B., Uprety, N., Wang, F., Huang, Y., Gabrusiewicz, K., Miao, Q., Dou, J., Alsuliman, A., Kerbauy, L. N., Acharya, S., Mohanty, V., Mendt, M., Li, S., Lu, J. J., ... Rezvani, K. (2021). Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells. Journal of Clinical Investigation, 131(14), Article e142116. https://doi.org/10.1172/JCI142116

@article{7c160606b20d46439a8976eeb3bb9038,

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

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.",

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

note = "Funding Information: This research was generously supported in part by Ann and Clarence Cazalot, the Dr. Marnie Rose Foundation, and the University of Texas MD Anderson Cancer Center Glioblastoma Moonshot Program. This work was funded by grants from the NIH (CA120813), the Specialized Program of Research Excellence (SPORE) in Brain Cancer grant (P50CA127001), and the NCI Cancer Center Support Grant (P30CA16672), which also supports the MD Anderson Flow Cytometry and Cellular Imaging Core Facility (FCCICF) that assisted with the CyTOF studies in this project. We thank our summer students Nadia Agha (University of Houston), Cindy Saliba (University of Iowa), and Lihi Shalev (Hebrew University of Jerusalem) for their assistance with some of the experiments performed in the study. Publisher Copyright: {\textcopyright} 2021, American Society for Clinical Investigation.",

year = "2021",

month = jul,

doi = "10.1172/JCI142116",

language = "English (US)",

volume = "131",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

number = "14",

}

Shaim, H, Shanley, M, Basar, R, Daher, M, Gumin, J, Zamler, DB, Uprety, N, Wang, F, Huang, Y, Gabrusiewicz, K, Miao, Q, Dou, J, Alsuliman, A, Kerbauy, LN, Acharya, S, Mohanty, V, Mendt, M, Li, S, Lu, JJ, Wei, J, Fowlkes, NW, Gokdemir, E, Ensley, EL, Kaplan, M, Kassab, C, Li, L, Ozcan, G, Banerjee, PP, Shen, Y, Gilbert, AL, Jones, CM, Bdiwi, M, Nunez-Cortes, AK, Liu, E, Yu, J, Imahashi, N, Muniz-Feliciano, L, Li, Y, Hu, J, Draetta, G, Marin, D, Yu, D, Mielke, S, Eyrich, M, Champlin, RE, Chen, K, Lang, FF, Shpall, EJ, Heimberger, AB & Rezvani, K 2021, 'Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells', Journal of Clinical Investigation, vol. 131, no. 14, e142116. https://doi.org/10.1172/JCI142116

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

AU - Miao, Qi

AU - Dou, Jinzhuang

AU - Alsuliman, Abdullah

AU - Kerbauy, Lucila N.

AU - Acharya, Sunil

AU - Mohanty, Vakul

AU - Mendt, Mayela

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 - Funding Information: This research was generously supported in part by Ann and Clarence Cazalot, the Dr. Marnie Rose Foundation, and the University of Texas MD Anderson Cancer Center Glioblastoma Moonshot Program. This work was funded by grants from the NIH (CA120813), the Specialized Program of Research Excellence (SPORE) in Brain Cancer grant (P50CA127001), and the NCI Cancer Center Support Grant (P30CA16672), which also supports the MD Anderson Flow Cytometry and Cellular Imaging Core Facility (FCCICF) that assisted with the CyTOF studies in this project. We thank our summer students Nadia Agha (University of Houston), Cindy Saliba (University of Iowa), and Lihi Shalev (Hebrew University of Jerusalem) for their assistance with some of the experiments performed in the study. 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.

UR - http://www.scopus.com/inward/record.url?scp=85109072960&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85109072960&partnerID=8YFLogxK

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 -

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

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this