Published ahead of print on April 7, 2004, doi:10.1164/rccm.200312-1683OC Am. J. Respir. Crit. Care Med., Volume 169, Number 12, June 2004, 1322-1330 A more recent version of this article appeared on June 15, 2004
Submitted on December 10, 2003 Cytotoxic T-cell Responses Against Mesothelioma by Apoptotic Cell-pulsed Dendritic CellsFrederic Ebstein1,1 Institute de Biologie, Unite Institut National de la Sante et de la Recherche Medicale, U601, Nantes, France, 2 Institute de Biologie, Unite Institut National de la Sante et de la Recherche Medicale, U601, Nantes, France; Service d'Oncologie Thoracique et Digestive, CHU Hotel Dieu, Nantes, France, 3 Service d'Oncologie Thoracique et Digestive, CHU Hotel Dieu, Nantes, France * To whom correspondence should be addressed. E-mail: marc.gregoire{at}nantes.inserm.fr.
Malignant pleural mesothelioma (MPM) is an uncommon tumor largely confined to the thoracic cavity which is resistant to conventional therapies, therefore prompting an intensive search for effective treatment alternatives. This study focuses on dendritic cell (DC) vaccination for MPM and evaluates the in vitro efficacy of antigen-loaded DC-based vaccines for the induction of major histocompatibility complex (MHC) class I-restricted anti-mesothelioma cytotoxic T lymphocyte (CTL) responses. The source of tumor-associated antigens (TAA) for HLA-A2+ DC from healthy donors were apoptotic HLA-A2- mesothelioma cells either lacking or expressing HSP70 according to whether tumor cells were heat shocked or not before UV-mediated apoptosis. Our results show that both apoptotic preparations were equivalent regarding to the responsiveness of DC to the combined treatment of TNFalpha and Poly(I:C), as determined by similar increased expressions of co-stimulatory molecules and IL-12 productions. However, only DC loaded with apoptotic HSP70-expressing cells were found to be potent in vitro inducers of CTL activity against HLA-A2+ mesothelioma cells. Such elicited CTL also exhibit cytotoxic activity against a HLA-A2+ melanoma cell line, suggesting recognition of shared antigens. These findings therefore carry the potential of offering an alternative promising approach for the therapy of patients with MPM. Key words: Mesothelioma, immunotherapy, dendritic cells, apoptotic cells and HSP
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