Published ahead of print on March 11, 2005, doi:10.1164/rccm.200501-057OC Am. J. Respir. Crit. Care Med., Volume 171, Number 10, May 2005, 1168-1177 A more recent version of this article appeared on May 15, 2005
Submitted on January 13, 2005 Immunotherapy of Murine Malignant Mesothelioma Using Tumor Lysate-pulsed Dendritic CellsJoost PJJ Hegmans1*,1 Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands * To whom correspondence should be addressed. E-mail: j.hegmans{at}erasmusmc.nl.
Rationale: Exploiting the immunostimulatory capacities of dendritic cells holds great promise for cancer immunotherapy. Currently, dendritic cell-based immunotherapy is evaluated clinically in a number of malignancies including melanoma, urogenital and lung cancer, showing variable but promising results. Objective: To evaluate if pulsed dendritic cells induce protective immunity against malignant mesothelioma in a mouse model. Methods: Malignant mesothelioma was induced in mice by intraperitoneal injection of the AB1 mesothelioma cell line, leading to death within 28 days. For immunotherapy, dendritic cells were pulsed overnight either with AB1 tumor cell line lysate, AB1-derived exosomes, or ex vivo AB1 tumor lysate and injected either before (day -14 and -7) at the day of (day 0) or after (day +1 and +8) tumor implantation. Main results: Mice receiving tumor lysate-pulsed dendritic cells prior to tumor implantation demonstrated protective anti-tumor immunity with prolonged survival (> 3 months) and even resisted secondary tumor challenge. Tumor protection was associated with strong tumor-specific cytotoxic T lymphocyte responses. Adoptive transfer of splenocytes or purified CD8+ T lymphocytes transferred tumor protection to unimmunized mice in vivo. When given after tumor implantation in a therapeutic setting, pulsed dendritic cells prevented mesothelioma outgrowth. With higher tumor load and delayed administration after tumor implantation, dendritic cells were no longer effective. Conclusions: We demonstrate in this murine model that immunotherapy using pulsed dendritic cells may emerge as a powerful tool to control mesothelioma outgrowth. In the future, immunotherapy using dendritic cells could be used as adjuvant to control local recurrence after multimodality treatment for malignant mesothelioma. Key words: cancer, dendritic cells, mesothelioma, immunotherapy, DC-based vaccines
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