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Cell Rep. Med., December 04, 2024 | https://doi.org/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,1,2,7 Weiwei Lin,3,4,7 Xiong Jin,1,5,7 Rui Niu,1,2 Zheng Yuan,1,2 Tianran Chai,1,2,6 Qi Zhang,1,2 Meixia Guo,1,2 Sung Soo Kim,6 Meichen Liu,1,2,6 Yilin Deng,1,2,6 Jong Bae Park,4,6 Sun Il Choi,1,5,* Bingyang Shi,1,2,* and Jinlong Yin 1,2,8,*
1The Zhongzhou Laboratory for Integrative Biology, Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China
2Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China
3Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, China
4Research Institute, National Cancer Center, Goyang, Gyeonggi 10408, Republic of Korea
5School of Pharmacy, Henan University, Kaifeng, Henan 475004, China
6Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Republic of Korea
7These authors contributed equally
8Lead contact
2Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China
3Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, China
4Research Institute, National Cancer Center, Goyang, Gyeonggi 10408, Republic of Korea
5School of Pharmacy, Henan University, Kaifeng, Henan 475004, China
6Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Republic of Korea
7These authors contributed equally
8Lead contact
*Corresponding authors: correspondence to Sun Il Choi, Bingyang Shi or Jinlong Yin
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.
논문정보
- Research article
- 2024년 12월 (BRIC 등록일 2025-01-10)
- 국내+국외 연구진
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