An mRNA vaccine encoding proteasome-targeted antigen enhances CD8+ T cell immunity

Abstract

The efficient induction of antigen-specific CD8⁺ T cell activation is crucial in the development of mRNA tumor vaccines. Endogenous antigens are primarily degraded through the ubiquitin-proteasome system, followed by antigen presentation via major histocompatibility complex class I (MHC-I) molecules, leading to the activation of CD8⁺ T cells. Therefore, in this study, a novel mRNA vaccine was developed by fusing the mRNA sequence encoding the antigen with a proteasome-targeting peptide (PTP), aiming to enhance proteasomal targeting of the antigen and facilitate its degradation through the ubiquitin-proteasome system, thereby inducing a stronger CD8⁺ T cell immune response. This study confirmed a significant increase in antigen expression of the antigen-PTP fused mRNA vaccine upon treatment with a VHL inhibitor, as well as notable upregulation of genes associated with the MHC-I antigen-presenting pathway following treatment with the antigen-PTP fused mRNA vaccine. The intramuscular administration of the antigen-PTP fused mRNA vaccine significantly promoted the activation of dendritic cells, macrophages, and T cells in draining lymph nodes and spleens. Additionally, in TC-1 tumor-bearing mice, it markedly suppressed tumor growth, facilitated infiltration of intratumoral antigen-specific CD8⁺ T cells, and induced immune memory.