TY - JOUR T1 - Depletion of tumor-associated macrophages with a CSF-1R kinase inhibitor enhances antitumor immunity and survival induced by DC immunotherapy JF - Cancer Immunology Research JO - Cancer Immunol Res DO - 10.1158/2326-6066.CIR-16-0309 SP - canimm.0309.2016 AU - Dammeijer, Floris AU - Lievense, Lysanne A. AU - Kaijen-Lambers, Margaretha E H AU - van Nimwegen, Menno AU - Bezemer, Koen AU - Hegmans, Joost P AU - van Hall, Thorbald AU - Hendriks, Rudi W AU - Aerts, Joachim G. Y1 - 2017/01/01 UR - http://cancerimmunolres.aacrjournals.org/content/early/2017/05/23/2326-6066.CIR-16-0309.abstract N2 - New immunotherapeutic strategies are needed to induce effective anti-tumor immunity in all cancer patients. 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. We show that M-CSFR-inhibition using the CSF-1R kinase inhibitor PLX3397 (pexidartinib) effectively reduced numbers of TAMs, circulating nonclassical monocytes, as well as amount of neo-angiogenesis and ascites in mesothelioma mouse models, but did not improve survival. When combined with dendritic cell vaccination, survival was synergistically enhanced with a concomitant decrease in TAMs and an increase in CD8+ T-cell numbers and functionality. Total as well as tumor antigen-specific CD8+ T cells in tumor tissue of mice treated with combination therapy showed reduced surface expression of the programmed cell death protein-1 (PD-1), a phenomenon associated with T-cell exhaustion. Finally, mice treated with combination therapy were protected from tumor rechallenge and displayed superior T-cell memory responses. We report that decreasing local TAM-mediated immune suppression without immune activation does not improve survival. However, combination of TAM-mediated immune suppression with dendritic cell immunotherapy generates robust and durable antitumor immunity. These findings provide insights into the interaction between immunotherapy induced anti-tumor T cells and TAMs and offers a therapeutic strategy for mesothelioma treatment. ER -