CD97 maintains tumorigenicity of glioblastoma stem cells via mTORC2 signaling and is targeted by CAR Th9 cells

Shuchang Zhou; Weiwei Lin; Xiong Jin; Rui Niu; Zheng Yuan; Tianran Chai; Qi Zhang; Meixia Guo; Sung Soo Kim; Meichen Liu; Yilin Deng; Jong Bae Park; Sun Il Choi; Bingyang Shi; Jinlong Yin

doi:10.1016/j.xcrm.2024.101844

CD97 maintains tumorigenicity of glioblastoma stem cells via mTORC2 signaling and is targeted by CAR Th9 cells

Shuchang Zhou, Weiwei Lin, Xiong Jin, Rui Niu, Zheng Yuan, Tianran Chai, Qi Zhang, Meixia Guo, Sung Soo Kim, Meichen Liu, Yilin Deng, Jong Bae Park, Sun Il Choi^*, Bingyang Shi^*, Jinlong Yin^*

^*Corresponding author for this work

Macquarie Medical School

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

3 Citations (Scopus)

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Abstract

Glioblastoma (GBM) stem cells (GSCs) contribute to poor prognosis in patients with GBM. Identifying molecular markers is crucial for developing targeted therapies. Here, we identify cluster of differentiation 97 (CD97) as an optimal GSC surface antigen for potential targeting by chimeric antigen receptor (CAR) T cell therapy through in vitro antibody screening. CD97 is consistently expressed in all validated patient-derived GSCs and positively correlated with known intracellular GSC markers. Silencing CD97 reduces GSC tumorigenicity-related activities, including self-renewal, proliferation, and tumor progression. Transcriptome analysis reveals that CD97 activates mTORC2, leading to AKT S473 phosphorylation and enhanced expression of the downstream genes ARHGAP1, BZW1, and BZW2. Inhibiting mTORC2 with JR-AB2-011 suppresses GSC tumorigenicity and downstream gene expression. We develop CD97-CAR T helper (Th) 9 cells, which exhibit potent cytotoxic effects in vitro and extend survival in mice. These findings suggest that CD97 is a promising GSC-enriched antigen and that targeting it with CAR Th9 cells offers a potential therapeutic strategy for GBM.

Original language	English
Article number	101844
Pages (from-to)	1-17
Number of pages	27
Journal	Cell Reports Medicine
Volume	5
Issue number	12
DOIs	https://doi.org/10.1016/j.xcrm.2024.101844
Publication status	Published - 17 Dec 2024

Bibliographical note

Copyright the Author(s) 2024. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

CAR T
CD97
glioblastoma
glioblastoma stem cell
mTORC2
self-renewal
Th9 cell
tumorigenicity

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10.1016/j.xcrm.2024.101844Licence: CC BY-NC-ND

Publisher version (open access)Final published version, 7.89 MBLicence: CC BY-NC-ND

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title = "CD97 maintains tumorigenicity of glioblastoma stem cells via mTORC2 signaling and is targeted by CAR Th9 cells",

abstract = "Glioblastoma (GBM) stem cells (GSCs) contribute to poor prognosis in patients with GBM. Identifying molecular markers is crucial for developing targeted therapies. Here, we identify cluster of differentiation 97 (CD97) as an optimal GSC surface antigen for potential targeting by chimeric antigen receptor (CAR) T cell therapy through in vitro antibody screening. CD97 is consistently expressed in all validated patient-derived GSCs and positively correlated with known intracellular GSC markers. Silencing CD97 reduces GSC tumorigenicity-related activities, including self-renewal, proliferation, and tumor progression. Transcriptome analysis reveals that CD97 activates mTORC2, leading to AKT S473 phosphorylation and enhanced expression of the downstream genes ARHGAP1, BZW1, and BZW2. Inhibiting mTORC2 with JR-AB2-011 suppresses GSC tumorigenicity and downstream gene expression. We develop CD97-CAR T helper (Th) 9 cells, which exhibit potent cytotoxic effects in vitro and extend survival in mice. These findings suggest that CD97 is a promising GSC-enriched antigen and that targeting it with CAR Th9 cells offers a potential therapeutic strategy for GBM.",

keywords = "CAR T, CD97, glioblastoma, glioblastoma stem cell, mTORC2, self-renewal, Th9 cell, tumorigenicity",

author = "Shuchang Zhou and Weiwei Lin and Xiong Jin and Rui Niu and Zheng Yuan and Tianran Chai and Qi Zhang and Meixia Guo and Kim, {Sung Soo} and Meichen Liu and Yilin Deng and Park, {Jong Bae} and Choi, {Sun Il} and Bingyang Shi and Jinlong Yin",

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doi = "10.1016/j.xcrm.2024.101844",

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AU - Zhou, Shuchang

AU - Lin, Weiwei

AU - Jin, Xiong

AU - Niu, Rui

AU - Yuan, Zheng

AU - Chai, Tianran

AU - Zhang, Qi

AU - Guo, Meixia

AU - Kim, Sung Soo

AU - Liu, Meichen

AU - Deng, Yilin

AU - Park, Jong Bae

AU - Choi, Sun Il

AU - Shi, Bingyang

AU - Yin, Jinlong

N1 - Copyright the Author(s) 2024. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2024/12/17

Y1 - 2024/12/17

N2 - Glioblastoma (GBM) stem cells (GSCs) contribute to poor prognosis in patients with GBM. Identifying molecular markers is crucial for developing targeted therapies. Here, we identify cluster of differentiation 97 (CD97) as an optimal GSC surface antigen for potential targeting by chimeric antigen receptor (CAR) T cell therapy through in vitro antibody screening. CD97 is consistently expressed in all validated patient-derived GSCs and positively correlated with known intracellular GSC markers. Silencing CD97 reduces GSC tumorigenicity-related activities, including self-renewal, proliferation, and tumor progression. Transcriptome analysis reveals that CD97 activates mTORC2, leading to AKT S473 phosphorylation and enhanced expression of the downstream genes ARHGAP1, BZW1, and BZW2. Inhibiting mTORC2 with JR-AB2-011 suppresses GSC tumorigenicity and downstream gene expression. We develop CD97-CAR T helper (Th) 9 cells, which exhibit potent cytotoxic effects in vitro and extend survival in mice. These findings suggest that CD97 is a promising GSC-enriched antigen and that targeting it with CAR Th9 cells offers a potential therapeutic strategy for GBM.

AB - Glioblastoma (GBM) stem cells (GSCs) contribute to poor prognosis in patients with GBM. Identifying molecular markers is crucial for developing targeted therapies. Here, we identify cluster of differentiation 97 (CD97) as an optimal GSC surface antigen for potential targeting by chimeric antigen receptor (CAR) T cell therapy through in vitro antibody screening. CD97 is consistently expressed in all validated patient-derived GSCs and positively correlated with known intracellular GSC markers. Silencing CD97 reduces GSC tumorigenicity-related activities, including self-renewal, proliferation, and tumor progression. Transcriptome analysis reveals that CD97 activates mTORC2, leading to AKT S473 phosphorylation and enhanced expression of the downstream genes ARHGAP1, BZW1, and BZW2. Inhibiting mTORC2 with JR-AB2-011 suppresses GSC tumorigenicity and downstream gene expression. We develop CD97-CAR T helper (Th) 9 cells, which exhibit potent cytotoxic effects in vitro and extend survival in mice. These findings suggest that CD97 is a promising GSC-enriched antigen and that targeting it with CAR Th9 cells offers a potential therapeutic strategy for GBM.

KW - CAR T

KW - CD97

KW - glioblastoma

KW - glioblastoma stem cell

KW - mTORC2

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KW - Th9 cell

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ER -

CD97 maintains tumorigenicity of glioblastoma stem cells via mTORC2 signaling and is targeted by CAR Th9 cells

Abstract

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Keywords

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