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Mol Cancer Ther. 2016 Aug;15(8):1975-87. doi: 10.1158/1535-7163.MCT-15-0850. Epub 2016 Jun 2.

ERK1 as a Therapeutic Target for Dendritic Cell Vaccination against High-Grade Gliomas.

Author information

1
Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrueck Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
2
Department of Molecular Cell Biology and Gene Therapy, Humboldt-University Berlin and Max Delbrueck Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
3
Department of Pediatrics I, Neonatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
4
MRI TOOLs GmbH, Berlin, Germany.
5
Department of Neurology, Heinrich Heine University, Düsseldorf, Germany.
6
University Nice-Sophia Antipolis, Institute for Research on Cancer and Aging of Nice (IRCAN), Nice, France.
7
Department of Cellular Neurosciences, Max Delbrueck Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
8
Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrueck Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. sonia.waiczies@mdc-berlin.de.

Abstract

Glioma regression requires the recruitment of potent antitumor immune cells into the tumor microenvironment. Dendritic cells (DC) play a role in immune responses to these tumors. The fact that DC vaccines do not effectively combat high-grade gliomas, however, suggests that DCs need to be genetically modified specifically to promote their migration to tumor relevant sites. Previously, we identified extracellular signal-regulated kinase (ERK1) as a regulator of DC immunogenicity and brain autoimmunity. In the current study, we made use of modern magnetic resonance methods to study the role of ERK1 in regulating DC migration and tumor progression in a model of high-grade glioma. We found that ERK1-deficient mice are more resistant to the development of gliomas, and tumor growth in these mice is accompanied by a higher infiltration of leukocytes. ERK1-deficient DCs exhibit an increase in migration that is associated with sustained Cdc42 activation and increased expression of actin-associated cytoskeleton-organizing proteins. We also demonstrated that ERK1 deletion potentiates DC vaccination and provides a survival advantage in high-grade gliomas. Considering the therapeutic significance of these results, we propose ERK1-deleted DC vaccines as an additional means of eradicating resilient tumor cells and preventing tumor recurrence. Mol Cancer Ther; 15(8); 1975-87.

PMID:
27256374
DOI:
10.1158/1535-7163.MCT-15-0850
[Indexed for MEDLINE]
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