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

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.

Type I interferons in anticancer immunity

“…Moreover, the intratumoural injection of an mRNA encoding IFNβ fused to the ectodomain of transforming growth factorβ (TGFβ) receptor 2 (TGFBR2) significantly delayed tumour growth by enhancing the ability of TAAspecific CTLs to mediate cytotoxic effects, which was further potentiated by the blockade of PD1 (REF. 89). …”

Targeting TGF-β Signaling for Therapeutic Gain

“…DCs exposed to this fusokine take up the RNA by phagocytosis and express the encoded fusion protein, resulting in enhanced antigen-presenting capacity. The fusokine also attenuates the suppressor activity of myeloid-derived suppressor cells (MDSCs) after transfection of the encoding plasmid into these cells (Van Der Jeught et al 2014). It has been postulated that intratumoral delivery of this fusokine RNA might enhance antigen presentation, and thus tumor immunity after intratumoral injection in vivo, but this remains to be tested.…”

Intratumoral Delivery of TriMix mRNA Results in T-cell Activation by Cross-Presenting Dendritic Cells

“…Tumors that reached a volume of AE100 mm 3 as measured by caliper and determined by the formula for a prolate ellipsoid were injected with mRNA resuspended in 50 mL 0.8 Hartmann solution (23).…”