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Rapid αβ TCR-mediated responses in γδ T cells transduced with cancer-specific TCR genes

Gene Therapy volume 16, pages 620–628 (2009)Cite this article

Abstract

Adoptive T-cell transfer of in vitro cultured T cells derived from cancer patients with naturally developed immune responses has met with some success as an immunotherapeutic approach, although only a limited number of patients showed spontaneous immune responses. To find alternative ways, such as cancer-specific T-cell receptor (TCR) gene transfer, in preparation for sufficient numbers of antigen-specific T cells is an important issue in the field of adoptive T-cell therapy. Given the inherent disadvantage of αβ TCR transfer to other αβ T cells, namely the possible formation of mixed TCR heterodimers with endogenous α or β TCR, we employed γδ T cells as a target for retroviral transfer of cancer-specific TCR and examined whether γδ T cells were useful as an alternative population for TCR transfer. Although retroviral transduction to γδ T cells with TCR αβ genes alone, isolated from a MAGE-A4143–151-specific αβ CD8+ cytotoxic T lymphocyte (CTL) clone, did not provide sufficient affinity to recognize major histocompatibility (MHC)–peptide complexes due to the lack of CD8 co-receptor, γδ T cells co-transduced with TCR αβ and CD8 αβ genes acquired cytotoxicity against tumor cells and produced cytokines in both αβ- and γδ-TCR-dependent manners. Furthermore, αβ TCR and CD8-transduced γδ T cells, stimulated either through αβ TCR or γδ TCR, rapidly responded to target cells compared with conventional αβ T cells, reminiscent of γδ T cells. We propose αβ TCR-transduced γδ T cells as an alternative strategy for adoptive T-cell transfer.

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Abbreviations

2M3B1PP:

2-Methyl-3-Butenyl-1-Pyrophosphate

CTL:

Cytotoxic T lymphocytes

IFN:

Interferon

IL:

Interleukin

TAP:

Transporter associated with antigen processing

TCR:

T-cell receptor

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Acknowledgements

We thank C Hyuga, S Hori and Y Shirakura for their excellent technical support. This study was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan. AH, HN, JM, IK and HS designed the research and analyzed the data. AH, HN, JM, YT and HS wrote the paper. YT and NM contributed vital new reagents. AH, MH, SK, SO, HC and SSY performed the research.

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Authors and Affiliations

  1. Department of Immunno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan

    A Hiasa, M Hirayama, S Kitano & H Shiku

  2. Department of Cancer Vaccine, Mie University Graduate School of Medicine, Mie, Japan

    H Nishikawa, M Hirayama & H Shiku

  3. Center for Cell and Gene Therapy, Takara Bio Inc., Shiga, Japan

    S Okamoto, H Chono, S S Yu, J Mineno & I Kato

  4. Center for Innovation in Immmunoregulative Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Y Tanaka

  5. Department of Immunology and Cell Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Y Tanaka & N Minato

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  1. A Hiasa
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Correspondence to H Shiku.

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Hiasa, A., Nishikawa, H., Hirayama, M. et al. Rapid αβ TCR-mediated responses in γδ T cells transduced with cancer-specific TCR genes. Gene Ther 16, 620–628 (2009). https://doi.org/10.1038/gt.2009.6

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