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Induced pluripotent stem cell-derived dendritic cell vaccine therapy genetically modified on the ubiquitin-proteasome system

Gene Therapy volume 30, pages 552–559 (2023)Cite this article

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Abstract

We previously reported that dendritic cells (DCs) transduced with the full-length tumor-associated antigen (TAA) gene induced TAA-specific cytotoxic T lymphocytes (CTLs) to elicit antitumor responses. To overcome the issue of quantity and quality of DCs required for DC vaccine therapy, we focused on induced pluripotent stem cells (iPSCs) as a new tool for obtaining DCs and reported efficacy of iPSCs-derived DCs (iPSDCs). However, in clinical application of iPSDC vaccine therapy, further enhancement of the antitumor effect is necessary. In this study, we targeted mesothelin (MSLN) as a potentially useful TAA, and focused on the ubiquitin-proteasome system to enhance antigen-presenting ability of iPSDCs. The CTLs induced by iPSDCs transduced with MSLN gene (iPSDCs-MSLN) from healthy donors showed cytotoxic activity against autologous lymphoblastoid cells (LCLs) expressing MSLN (LCLs-MSLN). The CTLs induced by iPSDCs transduced ubiquitin-MSLN fusion gene exhibited higher cytotoxic activity against LCLs-MSLN than the CTLs induced by iPSDCs-MSLN. The current study was designed that peripheral T-cell tolerance to MSLN could be overcome by the immunization of genetically modified iPSDCs simultaneously expressing ubiquitin and MSLN, leading to a strong cytotoxicity against tumors endogenously expressing MSLN. Therefore, this strategy may be promising for clinical application as an effective cancer vaccine therapy.

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Fig. 1: Construction of recombinant adenovirus transduced ubiquitin and MSLN fusion gene.
Fig. 2: Expression of co-stimulatory molecules in MoDCs and iPSDCs.
Fig. 3: Expression of MSLN in genetically modified DCs, and cytotoxic activity of CTLs generated from DCs-MSLN.
Fig. 4: Expression of MSLN in genetically modified DCs, and Pentamer assay of MSLN specific CTLs generated from genetically modified DCs.
Fig. 5: Cytotoxic activity of CTLs generated from MoDCs-MSLN and MoDCs-UbMSLN against autologous LCLs-MSLN (Donor 1).

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Acknowledgements

We acknowledge proofreading and editing by Benjamin Phillis at the Clinical Study Support Center at Wakayama Medical University.

Funding

Ministry of Education, Culture, Sports, Science and Technology, Japan; Grant number: 20K09063.

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Authors and Affiliations

  1. Second Department of Surgery, Wakayama Medical University, Wakayama, Japan

    Shinta Tominaga, Toshiyasu Ojima, Motoki Miyazawa, Hiromitsu Iwamoto, Junya Kitadani, Shimpei Maruoka, Keiji Hayata & Hiroki Yamaue

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  1. Shinta Tominaga
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  2. Toshiyasu Ojima
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  3. Motoki Miyazawa
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  4. Hiromitsu Iwamoto
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  7. Keiji Hayata
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  8. Hiroki Yamaue
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Contributions

Study concept and design: ST, MM and TO. Acquisition of data: ST, MM, SM, and JK. Drafting of the manuscript: ST and TO. Critical revision of the manuscript for important intellectual content: HY. Administrative, technical and material support: SM, JK, and HI. Study supervision: HY.

Corresponding author

Correspondence to Toshiyasu Ojima.

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Competing interests

The authors declare no competing interests.

Ethics approval

This study has been approved by the Safety Committee for Genetic Recombination Experiments of this university (approval number: 2020-5). Only healthy volunteer specimens were used in this study.

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Tominaga, S., Ojima, T., Miyazawa, M. et al. Induced pluripotent stem cell-derived dendritic cell vaccine therapy genetically modified on the ubiquitin-proteasome system. Gene Ther 30, 552–559 (2023). https://doi.org/10.1038/s41434-023-00388-z

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