Immunotherapy of murine malignant mesothelioma using tumor lysate-pulsed dendritic cells.
BACKGROUND
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 and 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 (Days -14 and -7) at the day of (Day 0) or after (Days +1 and +8) tumor implantation.


RESULTS
Mice receiving tumor lysate-pulsed dendritic cells before tumor implantation demonstrated protective antitumor 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.
Hegmans
Joost P J J
JP
Department of Pulmonary Medicine, Erasmus MC, H-Ee2253a, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. j.hegmans@erasmusmc.nl
Hemmes
Annabrita
A
Aerts
Joachim G
JG
Hoogsteden
Henk C
HC
Lambrecht
Bart N
BN
D000818:Animals; D000951:Antigens, Neoplasm / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008654:Mesothelioma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016896:Treatment Outcome
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines