Survival of metastatic melanoma patients after dendritic cell vaccination correlates with expression of leukocyte phosphatidylethanolamine-binding protein 1/Raf kinase inhibitory protein
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Sonja I. Buschow1,2,*, Matteo Ramazzotti3,*, Inge M.J. Reinieren-Beeren1, Lucie M. Heinzerling4, Harm Westdorp1, Irene Stefanini3, Luca Beltrame5, Stanleyson V. Hato1, Eva Ellebaek6, Stefanie Gross4, Van Anh Nguyen7, Georg Weinlich7, Jiannis Ragoussis8,11, Dilair Baban8, Beatrice Schuler-Thurner4, Inge M. Svane6, Nikolaus Romani7, Jonathan M. Austyn9, I. Jolanda M. De Vries1, Gerold Schuler4,*, Duccio Cavalieri10,* and Carl G. Figdor1,*
1Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
2Department of Gastroenterology and Hepatology, Erasmus University Medical Center (Erasmus MC), Rotterdam, The Netherlands
3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
4Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen, Germany
5Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
6CCIT, Center for Cancer Immune Therapy, Department of Hematology and Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
7Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria
8Genomics Group, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
9Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
10Department of Biology, University of Florence, Firenze, Italy
11Current address: McGill University and Genome Quebec Innovation Centre, McGill University, Quebec, Canada
*These authors have contributed equally to this work
Sonja I. Buschow, email: S.Buschow@erasmusmc.nl
Carl G. Figdor, email: Carl.Figdor@radboudumc.nl
Keywords: melanoma, dendritic cell vaccination, immunotherapy, immune suppression, PEBP1
Received: December 22, 2016 Accepted: May 22, 2017 Published: June 27, 2017
Immunotherapy for metastatic melanoma offers great promise but, to date, only a subset of patients have responded. There is an urgent need to identify ways of allocating patients to the most beneficial therapy, to increase survival and decrease therapy-associated morbidity and costs. Blood-based biomarkers are of particular interest because of their straightforward implementation in routine clinical care. We sought to identify markers for dendritic cell (DC) vaccine-based immunotherapy against metastatic melanoma through gene expression analysis of peripheral blood mononuclear cells. A large-scale microarray analysis of 74 samples from two treatment centers, taken directly after the first round of DC vaccination, was performed. We found that phosphatidylethanolamine binding protein 1 (PEBP1)/ Raf Kinase inhibitory protein (RKIP) expression can be used to identify a significant proportion of patients who performed poorly after DC vaccination. This result was validated by q-PCR analysis on blood samples from a second cohort of 95 patients treated with DC vaccination in four different centers. We conclude that low PEBP1 expression correlates with poor overall survival after DC vaccination. Intriguingly, this was only the case for expression of PEBP1 after, but not prior to, DC vaccination. Moreover, the change in PEBP1 expression upon vaccination correlated well with survival. Further analyses revealed that PEBP1 expression positively correlated with genes involved in T cell responses but inversely correlated with genes associated with myeloid cells and aberrant inflammation including STAT3, NOTCH1, and MAPK1. Concordantly, PEBP1 inversely correlated with the myeloid/ lymphoid-ratio and was suppressed in patients suffering from chronic inflammatory disease.
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