mRNA Vaccines: Suppressing Expression in Hepatocytes Boosts Immunity, Revealing the Role of Cell-Specific Expression
Cell type: a hidden variable in vaccine immunity
A preclinical study found that suppressing mRNA expression in hepatocytes can strengthen the immune response to mRNA vaccines. Direct mRNA expression in professional antigen-presenting cells (pAPCs) was not essential for initially inducing an antigen-specific T-cell response.
Proteins encoded by mRNA vaccines can be produced in many cell types. However, how the cell in which they are expressed affects the immune response has not been fully understood. This study distinguished expression in professional antigen-presenting cells, muscle cells, and hepatocytes to examine the role of each cell type.
Using miRTs to regulate mRNA expression by cell type
The researchers inserted synthetic microRNA target sites (miRTs) into mRNA delivered by lipid nanoparticles (LNPs). The design selectively suppresses mRNA expression in professional antigen-presenting cells, muscle cells, or hepatocytes. It targets mRNA expression in those cells, not the cells themselves.
The results showed that an antigen-specific T-cell response was induced even without direct mRNA expression in professional antigen-presenting cells. mRNA expression in muscle cells induced similar or stronger immune responses, including in experiments related to SARS-CoV-2. The researchers suggested that antigen cross-presentation or cross-dressing may contribute more to immune priming than direct mRNA expression in professional antigen-presenting cells. However, the abstract did not establish the relative contributions of these two pathways. Nor should the finding that direct expression was not essential be interpreted to mean that professional antigen-presenting cells themselves are unnecessary.
By contrast, mRNA expression in hepatocytes suppressed antigen-specific T-cell responses. The PD-1/PD-L1 pathway appeared to contribute to this suppression in part.
In mice bearing lymphoma cells that express tumor-associated antigens (TAAs), a TAA mRNA vaccine containing miRTs designed to suppress expression in hepatocytes strengthened the immune response and reduced tumor burden. The abstract provided does not give specific numerical data on effect sizes or dosing conditions.
Cell-specific expression control as a vaccine design variable
The study provides evidence that understanding mRNA vaccine responses requires examining expression in cell types beyond professional antigen-presenting cells. Adding miRTs to regulate expression by cell type may increase or decrease the ability of mRNA–LNPs to induce immune responses.
Suppressing expression in hepatocytes is a strategy to consider in cancer vaccine design, but the reduction in tumor burden was demonstrated in a lymphoma mouse model. The available evidence cannot establish therapeutic efficacy or improved safety in humans. The abstract alone makes it difficult to assess the composition of the control groups, quantitative effects, or long-term responses, leaving potential clinical application for further study.
The study is described in the paper abstract published in Nature Biotechnology.
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.
In cancer vaccine development, the cell in which an antigen is produced can be considered a design variable alongside the choice of tumor antigen. For example, a follow-up preclinical study could compare tumor-antigen mRNA vaccine candidates with and without miRTs that suppress expression in hepatocytes, then assess antigen-specific T-cell responses and tumor burden. This is a follow-up preclinical evaluation scenario, supported by the lymphoma mouse findings in this study. However, the observation that direct expression in professional antigen-presenting cells was not essential must not be taken to mean that antigen-presentation functions themselves are unnecessary. Whether the same immune-modulating effect occurs in humans, and how expression control affects safety, require separate validation.