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Updated: Aug 17, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
Development of CAR-T cells specifically targeting cancer stem cell antigen DNAJB8 against solid tumours
Yuto Watanabe1,2, Tomohide Tsukahara3, Kenji Murata1
1Department of Pathology, Sapporo Medical University, School of Medicine, South-1, West-17, Chuo-ku, Sapporo, Hokkaido, 060-8556, Japan.
Background:
As therapy for solid tumours, various tumour antigens have been selected as targets, but CAR-T cells targeting these antigens have shown limited efficacy, in contrast to the effectiveness of CAR-T cells targeting haematological malignancies. In a previous report, we identified a cancer-testis antigen, DNAJB8. DNAJB8 plays a major role in tumorigenicity in cancer stem-like cells/cancer-initiating cells (CSCs/CICs). Here, we report a DNAJB8-reactive CAR yielding anti-tumour effects against renal cell carcinoma (RCC) and osteosarcoma.
Methods:
We constructed a second-generation chimeric antigen receptor (CAR) against HLA-A*24:02/DNAJB8-derived peptide (DNAJB_143) complex (B10 CAR). The reactivity of B10-CAR T cells against T2-A24 cells pulsed with the cognate peptide and an RCC and osteosarcoma cell lines were quantified. The effects of adoptive cell transfer (ACT) therapy were assessed using in vivo xenografted mice models.
Results:
B10 CAR-T cells recognised DNAJB8_143-pulsed T2-A24 cells and HLA-A*24:02(+)/DNAJB8(+) renal cell carcinoma and osteosarcoma cell lines. Moreover, ACT using B10 CAR-T cells showed anti-tumour effects against RCC and osteosarcoma cells.
Conclusion:
B10 CAR-T cells could show specific cytotoxicity against RCC and osteosarcoma cells in vitro and in vivo. B10 CAR-T cells targeting the CSC/CIC antigen DNAJB8 might be a candidate immunotherapy for carcinoma and sarcoma.
Insights
Chimeric antigen receptor T-cell (CAR-T) therapy targeting DNAJB8 shows promise for treating renal cell carcinoma and osteosarcoma. This DNAJB8-reactive CAR-T therapy demonstrated significant anti-tumour effects in preclinical models.
Area of Science:
- Immunotherapy
- Oncology
- Cancer Stem Cell Biology
Background:
- Chimeric antigen receptor T-cell (CAR-T) therapy shows limited efficacy against solid tumors compared to hematological malignancies.
- DNAJB8, a cancer-testis antigen, is crucial for the tumorigenicity of cancer stem-like cells/cancer-initiating cells (CSCs/CICs).
Purpose of the Study:
- To develop and evaluate a DNAJB8-reactive CAR-T therapy for solid tumors.
- To assess the anti-tumor effects of this novel CAR-T therapy against renal cell carcinoma (RCC) and osteosarcoma.
Main Methods:
- Constructed a second-generation CAR (B10 CAR) targeting the HLA-A*24:02/DNAJB8 complex.
- Quantified B10-CAR T-cell reactivity against target cells and assessed anti-tumor effects using in vivo xenograft models.
Main Results:
- B10 CAR-T cells specifically recognized and exhibited cytotoxicity against RCC and osteosarcoma cell lines.
- Adoptive cell transfer (ACT) with B10 CAR-T cells demonstrated significant anti-tumor effects in vivo.
Conclusions:
- B10 CAR-T cells show specific in vitro and in vivo anti-tumor activity against RCC and osteosarcoma.
- CAR-T cells targeting the CSC/CIC antigen DNAJB8 represent a potential immunotherapy for carcinomas and sarcomas.
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