1. Screening for lipid nanoparticles that modulate the immune activity of helper T cells towards enhanced antitumour activity.
- Author
-
Zhu Y, Ma J, Shen R, Lin J, Li S, Lu X, Stelzel JL, Kong J, Cheng L, Vuong I, Yao ZC, Wei C, Korinetz NM, Toh WH, Choy J, Reynolds RA, Shears MJ, Cho WJ, Livingston NK, Howard GP, Hu Y, Tzeng SY, Zack DJ, Green JJ, Zheng L, Doloff JC, Schneck JP, Reddy SK, Murphy SC, and Mao HQ
- Subjects
- Animals, Mice, Lipids chemistry, Immunotherapy methods, Cancer Vaccines immunology, Cancer Vaccines administration & dosage, Female, Melanoma, Experimental immunology, Melanoma, Experimental therapy, Melanoma, Experimental drug therapy, Antigens, Neoplasm immunology, RNA, Messenger genetics, RNA, Messenger metabolism, Liposomes, Nanoparticles chemistry, Mice, Inbred C57BL, T-Lymphocytes, Helper-Inducer immunology, T-Lymphocytes, Helper-Inducer drug effects, Dendritic Cells immunology, Dendritic Cells drug effects
- Abstract
Lipid nanoparticles (LNPs) can be designed to potentiate cancer immunotherapy by promoting their uptake by antigen-presenting cells, stimulating the maturation of these cells and modulating the activity of adjuvants. Here we report an LNP-screening method for the optimization of the type of helper lipid and of lipid-component ratios to enhance the delivery of tumour-antigen-encoding mRNA to dendritic cells and their immune-activation profile towards enhanced antitumour activity. The method involves screening for LNPs that enhance the maturation of bone-marrow-derived dendritic cells and antigen presentation in vitro, followed by assessing immune activation and tumour-growth suppression in a mouse model of melanoma after subcutaneous or intramuscular delivery of the LNPs. We found that the most potent antitumour activity, especially when combined with immune checkpoint inhibitors, resulted from a coordinated attack by T cells and NK cells, triggered by LNPs that elicited strong immune activity in both type-1 and type-2 T helper cells. Our findings highlight the importance of optimizing the LNP composition of mRNA-based cancer vaccines to tailor antigen-specific immune-activation profiles., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2024
- Full Text
- View/download PDF