Molecular signatures associated with tumor-specific immune response in melanoma patients treated with dendritic cell-based immunotherapy
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Tamara García-Salum1,2, Andrea Villablanca1,2, Franziska Matthäus3, Andrés Tittarelli1,2, Mauricio Baeza4, Cristián Pereda1,2, M. Alejandra Gleisner1,2, Fermín E. González2,5, Mercedes N. López1,2, Jörg D. Hoheisel6, Johannes Norgauer7, Peter J. Gebicke-Haerter1,8 and Flavio Salazar-Onfray1,2
1Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, 8380453 Santiago, Chile
2Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, Universidad de Chile, 8380453 Santiago, Chile
3Faculty of Biological Sciences and FIAS, University of Frankfurt, Ruth-Moufang-Straße 1, 60438 Frankfurt am Main, Germany
4Laboratory of Periodontal Biology, Faculty of Dentistry, Universidad de Chile, 8380492 Santiago, Chile
5Laboratory of Experimental Immunology and Cancer, Faculty of Dentistry, Universidad de Chile, 8380492 Santiago, Chile
6Functional Genome Analysis, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
7Department of Dermatology, Jena University Hospital D-07743 Jena, Germany
8Institute of Psychopharmacology, Central Institute of Mental Health, University of Heidelberg, J5, 68159 Mannheim, Germany
Flavio Salazar-Onfray, email: [email protected]
Keywords: molecular signatures; immunotherapy; melanoma; CXCR4; CD32
Received: July 28, 2017 Accepted: February 26, 2018 Published: March 30, 2018
Purpose: We previously showed that autologous dendritic cells (DCs) loaded with an allogeneic heat shock (HS)-conditioned melanoma cell-derived lysate, called TRIMEL, induce T-cell-mediated immune responses in stage IV melanoma patients. Importantly, a positive delayed-type hypersensitivity (DTH) reaction against TRIMEL after vaccination, correlated with patients prolonged survival. Furthermore, we observed that DTH reaction was associated with a differential response pattern reflected in the presence of distinct cell subpopulations in peripheral blood. Detected variations in patient responses encouraged molecular studies aimed to identify gene expression profiles induced after vaccination in treated patients, allowing the identification of new molecular predictive markers.
Methods: Gene expression patterns were analyzed by microarrays during vaccination, and some of them confirmed by quantitative real-time reverse transcriptase PCR (qRT-PCR) in the total leukocyte population of a representative group of responder and non-responder patients. New candidates for biomarkers with predictive value were identified using bioinformatics, molecular analysis, and flow cytometry.
Results: Seventeen genes overexpressed in responder patients after vaccination respect to non-responders were identified after a mathematical analysis, from which ten were linked to immune responses and five related to cell cycle control and signal transduction. In immunological responder patients, increased protein levels of the chemokine receptor CXCR4 and the Fc-receptor CD32 were observed on cell membranes of CD8+ T and B cells and the monocyte population, respectively, confirming gene expression results.
Conclusions: Our study contributes to finding new molecular markers associated with clinical outcome and better understanding of clinically relevant immunological responses induced by anti-tumor DC-vaccines.
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