Development of a lymph node-homing peptide vaccine targeting C-C chemokine receptor 7-positive dendritic cells with enhanced antitumor immunity.

Targeting dendritic cells via surface receptors presents a promising strategy to enhance antigen delivery and antitumor immunity. C-C Chemokine Receptor 7 (CCR7), as a chemokine receptor, plays a crucial role in dendritic cells migration and homing to lymph node, making it an attractive target for the development of dendritic cell-targeted immunotherapies. In this study, using phage display technology and binding assay, a novel peptide, CRBP3, that specifically targeting CCR7 was identified. In vitro, CRBP3 efficiently bound to and was internalized by both immature and mature dendritic cells. Upon footpad administration, CRBP3 showed its capacity to accumulate into the popliteal lymph nodes. When conjugated to the antigenic peptide OVA257-264, the peptide vaccine (CRBP3-OVA257-264) significantly enhanced the formation of peptide/ major histocompatibility complex class I (MHC-I) complexes on the dendritic cell surface and promoted interferon-gamma (IFN-γ) production and proliferation of antigen-specific CD8+ T cells, regardless of dendritic cell maturation status. Importantly, CRBP3 conjugated peptide vaccines carrying the exogenous OVA257-264 peptide and endogenous HPV16 E749-57 peptide respectively demonstrated potent antitumor immune responses in anti-programmed cell death protein 1 (anti-PD-1) blockade responsive B16-OVA and anti-PD-1 resistant TC-1 tumor models. Notably, the CRBP3-E749-57 peptide vaccine induced complete tumor regression in TC-1 tumor bearing mice and conferred long-lasting protection against tumor rechallenge. These findings highlight the potential of CCR7-targeting peptides as versatile tools for lymph node-directed cancer immunotherapy.