Macrophage depletion attenuates murine mesothelioma phenotype but requires dendritic cell immunotherapy to induce anti-tumor immunity and extend survival
Floris Dammeijer, Lysanne Lievense, Margaretha Lambers, Menno van Nimwegen, Rachid Bouzid, Joost Hegmans, Rudi Hendriks†, Joachim Aerts†*
Department of Pulmonary Medicine, Erasmus MC Rotterdam, The Netherlands
Malignant mesothelioma is characterized by a poor prognosis and resistance to conventional therapies. Infiltration of tumor associated macrophages (TAM) is prominent in mesothelioma and is linked to immune suppression, angiogenesis and tumor aggressiveness. Therefore, TAM depletion could potentially reactivate anti-tumor immunity and improve dendritic cell-therapy efficacy.
Immune competent mice were orthotopically injected with syngeneic mesothelioma cell lines. On day 10, mice were treated with a macrophage colony-stimulating factor receptor (M-CSFR) inhibitor (PLX3397) for the duration of the experiment, with a single dose of DC-therapy or a combination of the two. Mice were monitored for survival and blood was obtained 5 days after start of therapy and analyzed by FACS. In other experiments, tumor and spleen were extracted 5 days after start of therapy to investigate the effects of treatment using FACS and immunohistochemistry. Finally, surviving mice were rechallenged to assess disease protection and recall responses in blood.
M-CSFR-inhibition effectively reduced TAMs, circulating non-classical monocytes, tumor-angiogenesis and ascites in mesothelioma models, but did not improve survival. When combined with DC-therapy, survival was synergistically enhanced with a decrease in TAMs and an increase in CD8+ T-cell numbers and functionality. Finally, mice treated with DC mono- or combination therapy were protected after tumor rechallenge with combination therapy treated mice displaying superior T-cell memory responses in blood compared to DC-therapy only treated mice.
These data indicate that decreasing local immune suppression without proper immune activation does not improve survival but when combined with cellular immunotherapy it generates robust and durable antitumor immunity.