mRNA vaccine immunity is enhanced by hepatocyte detargeting and not dependent on dendritic cell expression
(1) Marks A (2) Siu S (3) Bianchini F (4) Wang C (5) Lakshmi A (6) Phelan M (7) Zhu A (8) Moon C (9) Morla-Folch J (10) Teunissen AJP (11) Amabile A (12) Baccarini A (13) Merad M (14) Brody JD (15) Dong Y (16) Brown BD
To study how cell type-specific expression on mRNA-encoded proteins influences immunity, Marks and Siu et al. incorporated synthetic microRNA target sites into the mRNA. LNP-delivered mRNA did not need to be directly expressed in professional APCs (pAPCs), and expression in muscle cells was sufficient or stronger in immune response induction than pAPCs. mRNA expression in hepatocytes dampened the CD8+ T cell response and reduced mRNA vaccine control of tumor growth. Silencing mRNA expression in hepatocytes reversed these effects and, when mRNA vaccines were used to expand transferred T cells, reduced liver T cell infiltration and toxicity.
Contributed by Ute Burkhardt
(1) Marks A (2) Siu S (3) Bianchini F (4) Wang C (5) Lakshmi A (6) Phelan M (7) Zhu A (8) Moon C (9) Morla-Folch J (10) Teunissen AJP (11) Amabile A (12) Baccarini A (13) Merad M (14) Brody JD (15) Dong Y (16) Brown BD
To study how cell type-specific expression on mRNA-encoded proteins influences immunity, Marks and Siu et al. incorporated synthetic microRNA target sites into the mRNA. LNP-delivered mRNA did not need to be directly expressed in professional APCs (pAPCs), and expression in muscle cells was sufficient or stronger in immune response induction than pAPCs. mRNA expression in hepatocytes dampened the CD8+ T cell response and reduced mRNA vaccine control of tumor growth. Silencing mRNA expression in hepatocytes reversed these effects and, when mRNA vaccines were used to expand transferred T cells, reduced liver T cell infiltration and toxicity.
Contributed by Ute Burkhardt
ABSTRACT: 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.
Author Info:
(1) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (2) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (4) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7) Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (9) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (10) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (11) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (12) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (13) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (14) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (15) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (16) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu.
