mRNA vaccine immunity is enhanced by hepatocyte target avoidance and does not rely on dendritic cell expression
Hidden variables in vaccine immunity: cell types
mRNA vaccines induce protein expression in a variety of cells, but the impact of the specific cell type on immunity has remained unclear. In particular, the roles of hepatocytes and professional antigen‑presenting cells (pAPCs) were of interest.
Innovative approach to alter cell targeting with miRT
The investigators inserted synthetic microRNA target sites (miRT) into LNP‑delivered mRNA to selectively silence expression in pAPCs, muscle cells (myocytes), or hepatocytes. They observed that T‑cell responses were robust even when mRNA expression was absent in pAPCs, and that antigen expressed in myocytes elicited even stronger immunity.
Does hepatocyte silencing suppress immunity?
When antigen was expressed in hepatocytes, antigen‑specific T‑cell responses were reduced via the PD‑1/PD‑L1 pathway, supporting the prevailing view that the liver creates an immunosuppressive environment.
Opening new avenues for cancer therapy
Administration of a tumor‑associated antigen (TAA) mRNA vaccine incorporating hepatocyte‑silencing miRT to lymphoma‑bearing mice markedly enhanced immune responses and reduced tumor burden. Leveraging cell‑target modulation in vaccine design could improve the efficacy of cancer immunotherapy.
Implications and future outlook
This work demonstrates that mRNA vaccines do not require expression in dendritic cells and that avoidance of hepatocyte targeting can enhance immunity, establishing a new paradigm. Future vaccine development may achieve more potent and safer immune responses by controlling cell‑type‑specific expression.
Proteins encoded by mRNA vaccines can be expressed by a diversity of transfected cell types but how cell-type-specific expression influences immunity is poorly understood. To investigate this, we incorporated synthetic microRNA target sites (miRT) into lipid nanoparticle (LNP)-delivered mRNA vaccines to silence mRNA expression specifically in professional antigen-presenting cells (pAPCs), hepatocytes or myocytes. We found that mRNA expression in pAPCs was dispensable for priming antigen-specific T cells, whereas mRNA expression in myocytes induced similar or stronger immune responses, including for SARS-CoV-2, suggesting that antigen cross-presentation or cross-dressing may be more impactful than direct mRNA expression in pAPCs. In contrast, mRNA expression in hepatocytes suppressed the antigen-specific T cell response, partly through PD1/PDL1. In mice bearing tumor-associated antigen (TAA)-expressing lymphoma cells, miRT-mediated hepatocyte-silenced TAA mRNA vaccine enhanced immune response and reduced tumor burden. Thus, non-pAPC expression shapes immunity to mRNA-encoded protein and inclusion of miRTs can boost or blunt mRNA-LNP immunogenicity.
This study resolves the issue of hepatocyte‑mediated immunosuppression in mRNA vaccines, paving the way for more effective vaccines and cancer therapeutics that can provide direct benefits to patients.