M-CSFR inhibition decreases tumor-associated macrophages in mesothelioma and improves the DC therapy induced CD8+ T-cell phenotype. M-CSFR inhibition decreases.

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M-CSFR inhibition decreases tumor-associated macrophages in mesothelioma and improves the DC therapy induced CD8+ T-cell phenotype. M-CSFR inhibition decreases tumor-associated macrophages in mesothelioma and improves the DC therapy induced CD8+ T-cell phenotype. Identical to previous experiments, CBA/J mice were intraperitoneally inoculated with tumor cells and treated on day 10 with either DC therapy or control PBS, and/or continuous PLX3397- or control treatment. Only now, mice were sacrificed on t = 15 days to examine the TME, blood and spleen in the different treatment groups. For D-E, mice were treated at day 15 with either PLX3397 and/or DC therapy and sacrificed 8 days later when tumors were harvested and analyzed. A, Tumors were extracted from the peritoneal cavity and weighed. B, Tumors were dissociated and single-cell suspensions that were stained and analyzed by flow cytometry. TAMs were divided into IL10-positive and -negative and denoted as percentage of non-lymphoid cells, to correct for changes in lymphoid cells due to treatment. C, Similar to B, CD8+ TILs) were identified. The distinction was made between “exhausted” [Program Death 1+ (PD-1), Lymphocyte-activating-gene 3+, (LAG3+) and Interferonγ (IFNγ] and “non-exhausted” (PD-1−, LAG3−, and IFNγ+) CD8+ TILs. Cells were depicted as percentage of total lymphoid cells, to correct for changes in the myeloid compartment due to treatment. D, The frequencies of WT-1 and Mesothelin-specific T cells were determined in the tumors of mice treated with or without PLX3397 and/or DC therapy using dextramers. E, Pie charts depicting the distribution of PD-1 expression on Mesothelin-specific CD8+ T cells in the tumors of mice untreated or treated with the different immunotherapies as monotherapy, or in combination. All data are displayed as dot plots or bar graphs including the median and error bars indicating interquartile range. Pie charts are used to display distribution of PD-1 expression on CD8+ T cells in the different treatment arms. Statistical significance was determined using the Mann–Whitney U test with P < 0.05 being statistically significant. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ns, not significant; DC-Tx, DC therapy; TAM, tumor-associated macrophage; IL10, Interleukin 10, WT1, Wilms Tumor 1; PD-1, programmed cell death protein 1; PD-1hi, PD-1-high; PD-1int, PD-1-intermediate; PD-1neg; PD-1-negative. Floris Dammeijer et al. Cancer Immunol Res 2017;5:535-546 ©2017 by American Association for Cancer Research