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Redirecting human CD4+ T lymphocytes to the MHC class I-restricted melanoma antigen MAGE-A1 by TCR αβ gene transfer requires CD8α

Gene Therapy volume 12, pages 140–146 (2005)Cite this article

Abstract

Adoptive immunotherapy involving the transfer of autologous tumor or virus-reactive T lymphocytes has demonstrated its effectiveness in the eradication of cancer and virally infected cells. Clinical trails and in vitro studies have focused on CD8+ cytotoxic T-cell receptor (TCR) αβ lymphocytes since these cells directly kill virally infected- and tumor cells after antigen-specific recognition via their TCR αβ. However, increasing evidence suggests that induction of sustained immunity against cancer and viral infections depends on the presence of tumor- or virus-specific CD4+ T lymphocytes, which are restricted by MHC class II. Here, we show that these MHC class II-restricted CD4+ T lymphocytes can efficiently be redirected to MHC class I-restricted tumor cells by retroviral introduction of an HLA-A1/MAGE-A1-specific chimeric two-chain TCR VαCαζ/VβCβζ (tcTCR/ζ). However, TCR-transduced CD4+ T lymphocytes were only able to specifically bind to HLA-A1/MAGE-A1 complexes and respond to HLA-A1+/MAGE-A1+ melanoma cells when the CD8α gene was cointroduced. These CD4+/CD8α+/TCRPOS T lymphocytes produce IFN-γ, TNFα and IL-2 when specifically stimulated via the introduced TCR with immobilized HLA-A1/MAGE-A1 complexes or HLA-A1+/MAGE-A1+ melanoma cells. Furthermore, introduction of the CD8α gene into TCRPOS T lymphocytes rendered these T lymphocytes cytotoxic for HLA-A1+/MAGE-A1+ melanoma cells. These results demonstrate that human CD4+ T lymphocytes when genetically grafted with an HLA-A1/MAGE-A1-specific TCR and CD8α are induced to kill and produce cytokines upon specific interaction with the relevant melanoma cells. Hence, CD4+ T lymphocytes, in addition to CD8+ T lymphocytes, may be critical effector cells for adoptive immuno-gene therapy to generate a sustained tumor-specific immune response in cancer patients.

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Authors and Affiliations

  1. Laboratory of Tumor Immunology, Department of Medical Oncology, ErasmusMC-Daniel den Hoed, Rotterdam, The Netherlands

    R Willemsen, C Ronteltap, M Heuveling, R Debets & R Bolhuis

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  1. R Willemsen
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  2. C Ronteltap
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  3. M Heuveling
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  4. R Debets
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  5. R Bolhuis
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Willemsen, R., Ronteltap, C., Heuveling, M. et al. Redirecting human CD4+ T lymphocytes to the MHC class I-restricted melanoma antigen MAGE-A1 by TCR αβ gene transfer requires CD8α. Gene Ther 12, 140–146 (2005). https://doi.org/10.1038/sj.gt.3302388

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