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Published ahead of print on April 7, 2004, doi:10.1164/rccm.200312-1683OC
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American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 1322-1330, (2004)
© 2004 American Thoracic Society

Original Article

Cytotoxic T Cell Responses against Mesothelioma by Apoptotic Cell-pulsed Dendritic Cells

Frédéric Ebstein, Carole Sapede, Pierre-Joseph Royer, Marie Marcq, Catherine Ligeza-Poisson, Isabelle Barbieux, Laurent Cellerin, Gérard Dabouis and Marc Grégoire

Unité INSERM U601, Institut de Biologie, and Service d'Oncologie Thoracique et Digestive, CHU Hôtel Dieu, Nantes, France

Correspondence and requests for reprints should be addressed to Marc Grégoire, Ph.D., INSERM U601, Institut de Biologie, 44093 Nantes Cedex 01, France. E-mail: marc.gregoire{at}nantes.inserm.fr

Malignant pleural mesothelioma 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 malignant pleural mesothelioma and evaluates the in vitro efficacy of antigen-loaded DC-based vaccines for the induction of major histocompatibility complex Class I-restricted antimesothelioma cytotoxic T lymphocyte responses. The source of tumor-associated antigens for HLA-A2+ DCs from healthy donors was apoptotic HLA-A2– mesothelioma cells either lacking or expressing heat shock protein 70 according to whether tumor cells were heat shocked or not before ultraviolet-mediated apoptosis. Our results show that both apoptotic preparations were equivalent regarding the responsiveness of DCs to combined treatment with tumor necrosis factor-{alpha} and poly(inosinic-cytidylic) acid, as determined by similar increased expression of costimulatory molecules and interleukin-12 production. However, only DCs loaded with apoptotic heat shock protein 70-expressing cells were found to be potent in vitro inducers of cytotoxic T lymphocyte activity against HLA-A2+ mesothelioma cells. Such elicited cytotoxic T lymphocytes also exhibit cytotoxic activity against an 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 malignant pleural mesothelioma.

Key Words: apoptotic cells • dendritic cells • heat shock proteins • immunotherapy • mesothelioma




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