Synergistic tumor immunological strategy by combining tumor nanovaccine with gene-mediated extracellular matrix scavenger

Abstract

The antitumor efficacy of tumor vaccines is often limited by weak T cell responses and poor activated T cells infiltration. Herein, we reported a novel synergistic strategy to simultaneously overcome these two obstacles to realize enhanced tumor elimination. To induce the robust T cell responses, we designed a minimalist tumor nanovaccine based on stepwise electrostatic interactions. The dual-functional delivery system PEI/CaCO₃ (polyethylenimine coated CaCO₃), could not only act as a vaccine carrier that absorbed antigen ovalbumin (OVA) and adjuvant unmethylated cytosine-phosphate-guanine (CpG) with high efficiency, but also work as an underlying adjuvant to activate bone marrow-derived dendritic cells (BMDCs). Therefore, the formed PEI/CaCO₃/OVA/CpG vaccines (NVs) realized the significant enhancement of both the BMDCs activation and the specific responses of T cells in vivo. In addition, to enhance the infiltration of activated T cells in the tumor sites, the Spam1 gene, which could express hyaluronidase (HAase), was explored using PEI as the gene carrier shielded with aldehyde modified polyethylene glycol (CHO-PEG-CHO) through pH responsive Schiff base bonds. PEG/PEI/pSpam1 (pSpam1@NPs) could achieve a high HAase expression in the tumor sites to further degrade the tumor extracellular matrix, thus promoting the infiltration of immune cells. Besides, the degradation of extracellular matrix increased blood perfusion and relieved the tumor hypoxia to modulate the immune-suppressive microenvironment. Highly enhanced antitumor efficiency and tumor re-challenge prevention were achieved by combined NVs with pSpam1@NPs in B16-OVA bearing mice. The facile synergistic strategy we presented here is expected to be further used for personalized immunotherapy in the future.

Keywords: CTL infiltration; ECM; Gene therapy; Immunotherapy; M2-like macrophages; Nanovaccines.