A DNA-Launched Nanoparticle Vaccine Elicits CD8+ T-cell Immunity to Promote In Vivo Tumor Control

Abstract

Cytolytic T cells (CTL) play a pivotal role in surveillance against tumors. Induction of CTL responses by vaccination may be challenging, as it requires direct transduction of target cells or special adjuvants to promote cross-presentation. Here, we observed induction of robust CTL responses through electroporation-facilitated, DNA-launched nanoparticle vaccination (DLnano-vaccines). Electroporation was observed to mediate transient tissue apoptosis and macrophage infiltration, which were deemed essential to the induction of CTLs by DLnano-vaccines through a systemic macrophage depletion study. Bolus delivery of protein nano-vaccines followed by electroporation, however, failed to induce CTLs, suggesting direct in vivo production of nano-vaccines may be required. Following these observations, new DLnano-vaccines scaffolding immunodominant melanoma Gp100 and Trp2 epitopes were designed and shown to induce more potent and consistent epitope-specific CTL responses than the corresponding DNA monomeric vaccines or CpG-adjuvanted peptide vaccines. DNA, but not recombinant protein, nano-vaccinations induced CTL responses to these epitopes and suppressed melanoma tumor growth in mouse models in a CD8+ T-cell–dependent fashion. Further studies to explore the use of DLnano-vaccines against other cancer targets and the biology with which they induce CTLs are important.

A synDNA vaccine delivering neoAg collections controls heterogenous, multifocal murine lung and ovarian tumors via robust T cell generation

“…The increased infiltration of antigen-presenting cells (APCs) is associated with an increased CD8 + T cell response. 27 In conclusion, we have shown the feasibility of targeting up to 40 neoantigens using a simple combination system. Multiple neoantigens were immunogenic in this approach, and the magnitude or type of immune response was independent of the size of the construct and the position of individual epitope within the vaccine.…”

“…The increased infiltration of antigen-presenting cells (APCs) is associated with an increased CD8 + T cell response. 27 …”

Structural identification of neutralizing antibodies induced by nucleic acid encoded native-like trimer

“…While both protein and DNA vaccination induced trimer-specific binding antibodies, DNA but not protein vaccination induced CD4 + and CD8 + T-cell responses as well as nAb responses. Differences in the mechanisms with which antigens traffic and present for protein versus DNA-encoded immunogens may underlie differential induction of immune phenotypes by these two routes of vaccination 56 . Protein antigens are supplied as a depot of soluble antigens and may rely on bulk flow in the lymphatic system for antigen trafficking 57 .…”

Identification of SARS-CoV-2 CTL epitopes for development of a multivalent subunit vaccine for COVID-19

“…For example, studies have shown that epitope-based vaccines can effectively elicit protective immune responses against various pathogens, such as HIV and influenza viruses ( Oyarzún and Kobe, 2016 ; Ben-Yedidia and Arnon, 2007 ). Delivery of epitopes as DNA vaccines ( Wilson et al, 2003 ) or DNA-launched nanoparticle vaccines ( Xu et al, 2020 ) are known to induce strong CTL responses.…”