2. Academic Validation
  3. CD97 maintains tumorigenicity of glioblastoma stem cells via mTORC2 signaling and is targeted by CAR Th9 cells

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

  • Cell Rep Med. 2024 Dec 17;5(12):101844. doi: 10.1016/j.xcrm.2024.101844.
Shuchang Zhou 1,  Weiwei Lin 2,  Xiong Jin 3,  Rui Niu 1,  Zheng Yuan 1,  Tianran Chai 4,  Qi Zhang 1,  Meixia Guo 1,  Sung Soo Kim 5,  Meichen Liu 4,  Yilin Deng 4,  Jong Bae Park 6,  Sun Il Choi 7,  Bingyang Shi 8,  Jinlong Yin 9
Affiliations

Affiliations

  • 1 The Zhongzhou Laboratory for Integrative Biology, Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China; Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China.
  • 2 Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, China; Research Institute, National Cancer Center, Goyang, Gyeonggi 10408, Republic of Korea.
  • 3 The Zhongzhou Laboratory for Integrative Biology, Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China; School of Pharmacy, Henan University, Kaifeng, Henan 475004, China.
  • 4 The Zhongzhou Laboratory for Integrative Biology, Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China; Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China; Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Republic of Korea.
  • 5 Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Republic of Korea.
  • 6 Research Institute, National Cancer Center, Goyang, Gyeonggi 10408, Republic of Korea; Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Republic of Korea.
  • 7 The Zhongzhou Laboratory for Integrative Biology, Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China; School of Pharmacy, Henan University, Kaifeng, Henan 475004, China. Electronic address: sunil.choi@hotmail.com.
  • 8 The Zhongzhou Laboratory for Integrative Biology, Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China; Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China. Electronic address: bs@henu.edu.cn.
  • 9 The Zhongzhou Laboratory for Integrative Biology, Henan Key Laboratory of Brain Targeted Bio-Nanomedicine, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China; Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan 475004, China. Electronic address: jlyin@henu.edu.cn.
PMID: 39637858 DOI: 10.1016/j.xcrm.2024.101844
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; Th9 cell; glioblastoma; glioblastoma stem cell; mTORC2; self-renewal; tumorigenicity.

Figures
Products
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    Product Name
    Description
    Target
    Research Area
  • HY-122022
    99.16%, mTORC2抑制剂
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