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

Correspondence: Dr RA Willemsen, Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC-Daniel den hoed, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands

Received 24 December 2003; Accepted 5 August 2004; Published online 21 October 2004.

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) lymphocytes since these cells directly kill virally infected- and tumor cells after antigen-specific recognition via their TCR . 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 VC/VC (tcTCR/). 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 CD8 gene was cointroduced. These CD4⁺/CD8⁺/TCR^POS T lymphocytes produce IFN-, TNF 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 CD8 gene into TCR^POS 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 CD8 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.