High-grade glioma associated immunosuppression does not prevent immune responses induced by therapeutic vaccines in combination with Treg depletion

Springer Science and Business Media LLC - 2018
Mario Löhr1, Benjamin Freitag2, Antje Technau2, Jürgen Krauss3, Camelia-Maria Monoranu4, Johannes Rachor2, Manfred B. Lutz5, Carsten Hagemann1, Almuth F. Kessler1, Thomas Linsenmann1, Matthias Wölfl2, Ralf-Ingo Ernestus1, Sabrina Engelhardt6, Götz Gelbrich6, Paul G. Schlegel2, Matthias Eyrich2
1Department of Neurosurgery, University Medical Center Würzburg, Würzburg, Germany
2Department of Pediatric Oncology, University Children’s Hospital Würzburg, Würzburg, Germany
3Department of Pediatric Neurosurgery, University Medical Center, Würzburg, Germany
4Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg, Germany
5Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
6Department of Epidemiology and Biostatistics, University Medical Center, Würzburg, Germany

Tóm tắt

High-grade gliomas (HGG) exert systemic immunosuppression, which is of particular importance as immunotherapeutic strategies such as therapeutic vaccines are increasingly used to treat HGGs. In a first cohort of 61 HGG patients we evaluated a panel of 30 hematological and 34 plasma biomarkers. Then, we investigated in a second cohort of 11 relapsed HGG patients receiving immunomodulation with metronomic cyclophosphamide upfront to a DC-based vaccine whether immune abnormalities persisted and whether they hampered induction of IFNγ+ T-cell responses. HGG patients from the first cohort showed increased numbers of leukocytes, neutrophils and MDSCs and in parallel reduced numbers of CD4+/CD8+ T-cells, plasmacytoid and conventional DC2s. MDSCs and T-cell alterations were more profound in WHO IV° glioma patients. Moreover, levels of MDSCs and epidermal growth factor were negatively associated with survival. Serum levels of IL-2, IL-4, IL-5 and IL-10 were altered in HGG patients, however, without any impact on clinical outcome. In the immunotherapy cohort, 6-month overall survival was 100%. Metronomic cyclophosphamide led to > 40% reduction of regulatory T cells (Treg). In parallel to Treg-depletion, MDSCs and DC subsets became indistinguishable from healthy controls, whereas T-lymphopenia persisted. Despite low T-cells, IFNγ-responses could be induced in 9/10 analyzed cases. Importantly, frequency of CD8+VLA-4+ T-cells with CNS-homing properties, but not of CD4+ VLA-4+ T-cells, increased during vaccination. Our study identifies several features of systemic immunosuppression in HGGs. Metronomic cyclophosphamide in combination with an active immunization alleviates the latter and the combined treatment allows induction of a high rate of anti-glioma immune responses.

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