Synergistic antitumor immune activation in melanoma using LA-PegPI polymeric gene vaccine in conjunction with PD-1 inhibition

Cancer gene vaccines are a promising avenue for cancer immunotherapy; however, their success depends not only on the gene construct itself but more critically on the efficacy and safety of the gene delivery vehicle. Targeting dendritic cells (DCs), the specialized antigen-presenting cells, has been recognized as an optimal approach for cancer gene vaccine delivery. We previously synthesized LA-PegPI, a lactose-conjugated copolymer acting as a ligand for DC-SIGN receptors on DCs, which has shown low toxicity and high-efficiency gene delivery capability both in vitro and in vivo. In this study, we examined the immune response and vaccination activities of LA-PegPI-based polyplexes for melanoma gene therapy, demonstrating that LA-PegPI serves as a safe, effective, and DC-targeting gene delivery vector. Importantly, LA-PegPI/pDNA polyplexes effectively induced the release of proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IL-12, in DCs and promoted DC maturation via activation of the TLR/MyD88-NF-κB signaling pathway. Furthermore, we employed an OVA-overexpressing melanoma mouse model to investigate the vaccination activities of LA-PegPI/pOVA polyplexes in vivo, revealing that subcutaneous injection significantly inhibited tumor growth and extended the survival of B16-OVA-bearing C57/BL6 mice and synergistically enhanced the antitumor activities of PD-1 inhibitors. We showed that LA-PegPI/pOVA polyplex injection increased the number of activated CD4+ T cells, CD8+ T cells, and NK cells, augmented the release of Th1 cytokines, and promoted the production of tumor-specific antibodies in this model, effects contributing to the antitumor immune response elicited by vaccination. Overall, LA-PegPI proves to be a safe and effective gene delivery vector with specific DC-targeting ability for cancer gene vaccines, and its potential clinical application warrants further investigation.