High-grade glioma associated immunosuppression does not prevent immune responses induced by vaccination with autologous, tumor-lysate pulsed dendritic cells

High-grade gliomas (HGG) are known to suppress anti-cancer immunity. In addition to local factors they also inhibit systemic immunity which could interfere with induction of immune responses by therapeutic vaccines. In a first cohort of 61 patients with HGG, we analyzed peripheral blood lymphocyte, monocyte and dendritic cell subsets as well as a panel of 36 biomarkers before and after neurosurgery. While leukocytes, neutrophils, and monocytic MDSCs were increased, CD4+ and CD8+ T-cells as well as plasmacytoid and myeloid DCs were decreased in HGG patients. B- and NK-cells were not affected. Multivariate analysis revealed that changes in leukocytes and neutrophils were more related to the use of dexamethasone, whereas monocytic MDSCs and lymphocyte numbers were significantly influenced by WHO grade (III° vs. IV°). Serum levels of IL-2, IL-4, IL-5, IL-10 and MACC1 were altered in HGG patients. EGF levels and monocytic MDSCs had a significant association with overall survival. Tumor resection had no immediate effect on any of these parameters. In a second cohort of 12 relapsed HGG patients treated with depletion of regulatory T-cells followed by DC-vaccinations after second resection we could demonstrate that levels of monocytic MDSCs and dendritic cell subsets normalized. Despite persisting T-lymphopenia, successful IFNγ-CTL responses could be induced in 10/12 (83%) of cases. During vaccination, number of CD8+VLA-4+ but not of CD4+VLA-4+ T-cells increased, VLA-4 being a key molecule for CNS entry. In conclusion we demonstrate that most of systemic immune impairments observed in HGG patients are reversible under immunotherapy and that successful anti-tumor immune responses can be induced by therapeutic vaccines despite persisting T-lymphopenia.