mRNA-LNP vaccines tuned for systemic immunization induce strong antitumor immunity by engaging splenic immune cells

mRNA vaccines have recently proved to be highly effective against SARS-CoV-2. Key to their success is the lipid-based nanoparticle (LNP), which enables efficient mRNA expression and endows the vaccine with adjuvant properties that drive potent antibody responses. Effective cancer vaccines require long-lived, qualitative CD8 T cell responses instead of antibody responses. Systemic vaccination appears to be the most effective route, but necessitates adaptation of LNP composition to deliver mRNA to antigen-presenting cells. Using a design-of-experiments methodology, we tailored mRNA-LNP composi-tions to achieve high-magnitude tumor-specific CD8 T cell responses within a single round of optimization. Optimized LNP compositions resulted in enhanced mRNA uptake by mul-tiple splenic immune cell populations. Type I interferon and phagocytes were found to be essential for the T cell response. Surprisingly, we also discovered a yet unidentified role of B cells in stimulating the vaccine-elicited CD8 T cell response. Optimized LNPs displayed a similar, spleen-centered bio-distribution profile in non-human primates and did not trigger histopathological changes in liver and spleen, warranting their further assessment in clinical studies. Taken together, our study clarifies the relationship between nanoparticle composi-tion and their T cell stimulatory capacity and provides novel insights into the underlying mechanisms of effective mRNA-LNP-based antitumor immunotherapy.

Automated summary

mRNA vaccines have shown high efficacy against SARS-CoV-2, attributed to lipid-based nanoparticles (LNPs) that enable efficient mRNA expression and adjuvant properties. Effective cancer vaccines necessitate long-lived, qualitative CD8 T cell responses. By optimizing LNP composition, researchers achieved high-magnitude tumor-specific CD8 T cell responses. Unexpectedly, they discovered a role of B cells in stimulating the vaccine-elicited CD8 T cell response. Optimized LNPs showed favorable biodistribution profiles in non-human primates and did not cause histopathological changes, calling for further evaluation in clinical studies.