Oncotarget

Research Papers:

Intratumoral administration of mRNA encoding a fusokine consisting of IFN-β and the ectodomain of the TGF-β receptor II potentiates antitumor immunity

Kevin Van der Jeught _, Patrick Tjok Joe, Lukasz Bialkowski, Carlo Heirman, Lidia Daszkiewicz, Therese Liechtenstein, David Escors, Kris Thielemans and Karine Breckpot

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Oncotarget. 2014; 5:10100-10113. https://doi.org/10.18632/oncotarget.2463

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Abstract

Kevin Van der Jeught1, Patrick Tjok Joe1, Lukasz Bialkowski1, Carlo Heirman1, Lidia Daszkiewicz1, Therese Liechtenstein2, David Escors2,3, Kris Thielemans1, Karine Breckpot1

1 Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, Belgium

2 Rayne Institute, University College London, London, UK

3 Biomedical Research Centre NavarraBiomed-Fundacion Miguel Servet, National Health Service of Navarre, Pamplona, Navarre, Spain

Correspondence to:

Dr. Karine Breckpot, e-mail: kbreckpo@vub.ac.be

Keywords: mRNA, IFN-β, TGF-β, cancer therapy, T cell

Received: July 04, 2014     Accepted: September 06, 2014     Published: September 19, 2014

ABSTRACT

It is generally accepted that the success of immunotherapy depends on the presence of tumor-specific CD8+ cytotoxic T cells and the modulation of the tumor environment. In this study, we validated mRNA encoding soluble factors as a tool to modulate the tumor microenvironment to potentiate infiltration of tumor-specific T cells. Intratumoral delivery of mRNA encoding a fusion protein consisting of interferon-β and the ectodomain of the transforming growth factor-β receptor II, referred to as Fβ2, showed therapeutic potential. The treatment efficacy was dependent on CD8+ T cells and could be improved through blockade of PD-1/PD-L1 interactions. In vitro studies revealed that administration of Fβ2 to tumor cells resulted in a reduced proliferation and increased expression of MHC I but also PD-L1. Importantly, Fβ2 enhanced the antigen presenting capacity of dendritic cells, whilst reducing the suppressive activity of myeloid-derived suppressor cells. In conclusion, these data suggest that intratumoral delivery of mRNA encoding soluble proteins, such as Fβ2, can modulate the tumor microenvironment, leading to effective antitumor T cell responses, which can be further potentiated through combination therapy.


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