Qu, Li et al. generated lipid nanoparticles (LNPs) encapsulating mRNA for cGAS, the innate immune sensor of cytoplasmic dsDNA. Human cGAS was mutated (K187N/L195R) to enhance its activation of the STING-dependent IFN response; induceAPC maturation, antigen uptake, and presentation; and upregulate expression of MHC-I, MHC-II, and costimulatory signals in vitro and in mice. Treating mice with mutated hcGASmRNA-LNPs induced strong innate and adaptive immune responses that boosted the potency of mRNA, protein, and tumor vaccines, and also synergized with IFNγ treatment to act directly on tumor cells to reduce tumor volume and increase host survival.
Contributed by Paula Hochman
ABSTRACT: mRNA vaccines are a potent tool for immunization against viral diseases and cancer. However, the lack of a vaccine adjuvant limits the efficacy of these treatments. In this study, we used cGAS mRNA, which encodes the DNA innate immune sensor, complexed with lipid nanoparticles (LNP), to boost the immune response. By introducing specific mutations in human cGAS mRNA (hcGASK187N/L195R), we significantly enhanced cGAS activity, resulting in a more potent and sustained stimulator of interferon gene (STING)-mediated IFN response. cGAS mRNA-LNPs exhibited stimulatory effects on maturation, antigen engulfment, and antigen presentation by antigen-presenting cells, both in vitro and in vivo. Moreover, the hcGASK187N/L195R mRNA-LNP combination demonstrated a robust adjuvant effect and amplified the potency of mRNA and protein vaccines, which was a result of strong humoral and cell-mediated responses. Remarkably, the hcGASK187N/L195R mRNA-LNP complex, either alone or in combination with antigens, demonstrated exceptional efficacy in eliciting antitumor immunity. In addition to its immune-boosting properties, hcGASK187N/L195R mRNA-LNP exerted antitumor effects with IFN_ directly on tumor cells, further promoting tumor restriction. In conclusion, we developed a cGAS mRNA-based immunostimulatory adjuvant compatible with various vaccine forms to boost the adaptive immune response and cancer immunotherapies.
Author Info: (1) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Cen
Author Info: (1) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science & Biomedicine IHM, Division of Life Sciences & Medicine, University of Science and Technology of China, Hefei, China. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (2) Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. Department of Radiology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (3) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science & Biomedicine IHM, Division of Life Sciences & Medicine, University of Science and Technology of China, Hefei, China. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (4) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science & Biomedicine IHM, Division of Life Sciences & Medicine, University of Science and Technology of China, Hefei, China. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (5) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science & Biomedicine IHM, Division of Life Sciences & Medicine, University of Science and Technology of China, Hefei, China. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (6) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science & Biomedicine IHM, Division of Life Sciences & Medicine, University of Science and Technology of China, Hefei, China. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (7) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science & Biomedicine IHM, Division of Life Sciences & Medicine, University of Science and Technology of China, Hefei, China. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (8) Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (9) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science & Biomedicine IHM, Division of Life Sciences & Medicine, University of Science and Technology of China, Hefei, China. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (10) The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (11) The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (12) Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (13) The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (14) Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. Department of Radiology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (15) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science & Biomedicine IHM, Division of Life Sciences & Medicine, University of Science and Technology of China, Hefei, China. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. (16) Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. Department of Radiology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (17) National Key Laboratory of Immune Response and Immunotherapy, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science & Biomedicine IHM, Division of Life Sciences & Medicine, University of Science and Technology of China, Hefei, China. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China.
