TLR9 plus STING Agonist Adjuvant Combination Induces Potent Neopeptide T Cell Immunity and Improves Immune Checkpoint Blockade Efficacy in a Tumor Model.
Melisa Daiana Castro EiroKou HiokiLing LiMerel E P WilmsenCaoimhe H KiernanInge Brouwers-HaspelsMarjan van MeursManzhi ZhaoHarm de WitDwin G B GrashofHarmen J G van de WerkenYvonne M MuellerChristopher SchlieheBurcu TemizozKouji KobiyamaKen J IshiiPeter D KatsikisPublished in: Journal of immunology (Baltimore, Md. : 1950) (2023)
Immune checkpoint blockade (ICB) immunotherapies have emerged as promising strategies for the treatment of cancer; however, there remains a need to improve their efficacy. Determinants of ICB efficacy are the frequency of tumor mutations, the associated neoantigens, and the T cell response against them. Therefore, it is expected that neoantigen vaccinations that boost the antitumor T cell response would improve ICB therapy efficacy. The aim of this study was to develop a highly immunogenic vaccine using pattern recognition receptor agonists in combination with synthetic long peptides to induce potent neoantigen-specific T cell responses. We determined that the combination of the TLR9 agonist K-type CpG oligodeoxynucleotides (K3 CpG) with the STING agonist c-di-AMP (K3/c-di-AMP combination) significantly increased dendritic cell activation. We found that immunizing mice with 20-mer of either an OVA peptide, low-affinity OVA peptides, or neopeptides identified from mouse melanoma or lung mesothelioma, together with K3/c-di-AMP, induced potent Ag-specific T cell responses. The combined K3/c-di-AMP adjuvant formulation induced 10 times higher T cell responses against neopeptides than the TLR3 agonist polyinosinic:polycytidylic acid, a derivative of which is the leading adjuvant in clinical trials of neoantigen peptide vaccines. Moreover, we demonstrated that our K3/c-di-AMP vaccine formulation with 20-mer OVA peptide was capable of controlling tumor growth and improving survival in B16-F10-OVA tumor-bearing C57BL/6 mice and synergized with anti-PD-1 treatment. Together, our findings demonstrate that the K3/c-di-AMP vaccine formulation induces potent T cell immunity against synthetic long peptides and is a promising candidate to improve neoantigen vaccine platform.
Keyphrases
- protein kinase
- biofilm formation
- early stage
- clinical trial
- inflammatory response
- toll like receptor
- dendritic cells
- drug delivery
- immune response
- anti inflammatory
- high glucose
- dna methylation
- randomized controlled trial
- staphylococcus aureus
- amino acid
- escherichia coli
- gene expression
- stem cells
- cystic fibrosis
- mesenchymal stem cells
- high throughput
- endothelial cells
- squamous cell
- candida albicans
- insulin resistance
- replacement therapy
- cell therapy
- phase ii