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Modified tumour antigen-encoding mRNA facilitates the analysis of naturally occurring and vaccine-induced CD4 and CD8 T cells in cancer patients

Knights, Ashley J.
Nuber, Natko
Thomson, Christopher W.
de la Rosa, O.
Jager, E.
van den Broek, M.
Pascolo, S.
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Published in Cancer immunology and immunotherapy. 2009, vol. 58, no. 3, p. 325-338
Abstract The development of effective anti-cancer vaccines requires precise assessment of vaccine-induced immunity. This is often hampered by low ex vivo frequencies of antigen-specific T cells and limited defined epitopes. This study investigates the applicability of modified, in vitro-transcribed mRNA encoding a therapeutically relevant tumour antigen to analyse T cell responses in cancer patients. In this study transfection of antigen presenting cells, by mRNA encoding the tumour antigen NY-ESO-1, was optimised and applied to address spontaneous and vaccine-induced T cell responses in cancer patients. Memory CD8+ T cells from lung cancer patients having detectable humoral immune responses directed towards NY-ESO-1 could be efficiently detected in peripheral blood. Specific T cells utilised a range of different T cell receptors, indicating a polyclonal response. Specific killing of a panel of NY-ESO-1 expressing tumour cell lines indicates recognition restricted to several HLA allelic variants, including a novel HLA-B49 epitope. Using a modified mRNA construct targeting the translated antigen to the secretory pathway, detection of NY-ESO-1-specific CD4+ T cells in patients could be enhanced, which allowed the in-depth characterisation of established T cell clones. Moreover, broad CD8+ and CD4+ T cell responses covering multiple epitopes were detected following mRNA stimulation of patients treated with a recombinant vaccinia/fowlpox NY-ESO-1 vaccine. This approach allows for a precise monitoring of responses to tumour antigens in a setting that addresses the breadth and magnitude of antigen-specific T cell responses, and that is not limited to a particular combination of known epitopes and HLA-restrictions.
Keywords Antibodies, Monoclonal/chemistryAntigens, Neoplasm/chemistry/*metabolismCD4-Positive T-Lymphocytes/*metabolismCD8-Positive T-Lymphocytes/*metabolismCancer VaccinesCarcinoma, Non-Small-Cell Lung/metabolismCell Line, TumorEpitopes/chemistryHumansInterferon-gamma/metabolismLung Neoplasms/metabolismModels, GeneticNeoplasms/*blood/*metabolismPeptides/chemistryRNA, Messenger/*metabolism
PMID: 18663444
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Research group Compatibilité tissulaire et transplantation clinique (562)
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KNIGHTS, Ashley J. et al. Modified tumour antigen-encoding mRNA facilitates the analysis of naturally occurring and vaccine-induced CD4 and CD8 T cells in cancer patients. In: Cancer immunology and immunotherapy, 2009, vol. 58, n° 3, p. 325-338. doi: 10.1007/s00262-008-0556-8 https://archive-ouverte.unige.ch/unige:19892

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Deposited on : 2012-04-23

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