APC-targeted DNA vaccines: the role of CCL19 in immune cell recruitment and early onset of the immune response

TL;DR

This study shows that fusing CCL19 with cancer antigens in DNA vaccines improves immune response and tumor control by recruiting immune cells more effectively.

Contribution

The study demonstrates that CCL19, when fused to neoantigens, retains its immune-recruiting properties and enhances DNA vaccine effectiveness.

Findings

CCL19 fusion constructs retained CCR7-dependent signaling and chemotaxis in dendritic cells.

In vivo, CCL19-fused vaccines recruited immune cells to the immunization site and improved tumor control.

CCL19-fused DNA vaccines induced earlier immune responses and greater anti-tumor efficacy.

Abstract

The introduction of DNA-encoded immune modulatory components is a promising strategy to enhance the immunogenicity of DNA vaccines. Antigen-presenting cell (APC)-targeted vaccines fuse DNA-encoded antigens with such adjuvants, fostering targeted immune activation. This study examined the cellular and molecular mechanisms of an APC-targeted DNA vaccine encoding Chemokine (C-C motif) ligand 19 (CCL19) fused to cancer neoantigens.

DNA vaccines encoding CCL19 fused to a dimerization domain and cancer neoantigens were tested both in vitro and in vivo. CCR7-mediated Gαi signaling, β-arrestin recruitment, and chemotaxis were evaluated in transfected cells and primary monocyte-derived dendritic cells. Protein expression and distribution were examined in vaccinated mice. The effect of CCL19 on vaccine-induced T-cell responses and anti-tumor efficacy was assessed in the CT26 syngeneic tumor model.

CCL19 retained its key biological functions when fused to cancer neoantigens, including CCR7-dependent signaling and chemotaxis of dendritic cells. In vivo, CCL19-fusion constructs were expressed locally and recruited immune cells to the immunization site. Tumor studies confirmed the superior immunogenicity and tumor control of the APC-targeted DNA vaccine, with CCL19 initiating an earlier immune response and enhancing anti-tumor effectiveness.

CCL19 serves as an effective APC-targeting unit when fused to neoantigens, maintaining chemotactic and signaling properties that improve DNA vaccine immunogenicity and tumor control. This chemokine-mediated strategy offers a flexible approach to increase DNA vaccine potency with broad potential applications in cancer immunotherapies and beyond.

The online version contains supplementary material available at 10.1007/s00262-026-04339-6.

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