In vitro transcribed mRNA constitutes a versatile platform to encode antigens
and to evoke CD8 T-cell responses. Systemic delivery of mRNA packaged
into cationic liposomes (lipoplexes) has proven particularly powerful
in achieving effective antitumor immunity in animal models. Yet, T-cell
responses to mRNA lipoplexes critically depend on the induction of
type I interferons (IFN), potent pro-inflammatory cytokines, which
inflict dose-limiting toxicities. Here, we explored an advanced hybrid
lipid polymer shell mRNA nanoparticle (lipopolyplex) endowed with
a trimannose sugar tree as an alternative delivery vehicle for systemic
mRNA vaccination. Like mRNA lipoplexes, mRNA lipopolyplexes were extremely
effective in conferring antitumor T-cell immunity upon systemic administration.
Conversely to mRNA lipoplexes, mRNA lipopolyplexes did not rely on
type I IFN for effective T-cell immunity. This differential mode of
action of mRNA lipopolyplexes enabled the incorporation of N1 methyl
pseudouridine nucleoside modified mRNA to reduce inflammatory responses
without hampering T-cell immunity. This feature was attributed to
mRNA lipopolyplexes, as the incorporation of thus modified mRNA into
lipoplexes resulted in strongly weakened T-cell immunity. Taken together,
we have identified lipopolyplexes containing N1 methyl pseudouridine
nucleoside modified mRNA as potent yet low-inflammatory alternatives
to the mRNA lipoplexes currently explored in early phase clinical
trials.
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.
Our results suggest that uptake of mRNA, encoding strong activation signals and a potent HIV antigen, confers a T-cell stimulatory capacity to dendritic cells and enhances their ability to stimulate antigen-specific immunity. These findings may pave the way for therapeutic HIV vaccine strategies based on antigen-encoding RNA to specifically target antigen-presenting cells.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.