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 1 , Patrick Tjok Joe 1 , Lukasz Bialkowski 1 , Carlo Heirman 1 , Lidia Daszkiewicz 1 , Therese Liechtenstein 2 , David Escors 2, 3 , Kris Thielemans 1 , Karine Breckpot 1 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 Fβ 2 , 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 Fβ 2 to tumor cells resulted in a reduced proliferation and increased expression of MHC I but also PD-L1. Importantly, Fβ 2 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 Fβ 2 , can modulate the tumor microenvironment, leading to effective antitumor T cell responses, which can be further potentiated through combination therapy.