Co-assembled and self-delivered epitope/CpG nanocomplex vaccine augments peptide immunogenicity for cancer immunotherapy

Abstract

Peptide vaccines are broadly used as alternatives to traditional vaccines for cancer immunotherapy; however, the clinical translation of peptide vaccination is still limited by the low antitumor CD8+ cytotoxic T-lymphocyte (CTL) response. Here, we report a facile, robust, and generalizable strategy for peptide vaccination to augment immunogenicity based on spontaneous non-covalent interactions between TLR9 agonist CpG and cell-penetrating peptide-conjugated epitope SIINFEKL, LCPGNKYEM, or SVYDFFVWL. The co-assembled epitope/CpG nanocomplex vaccine showed rapid endocytosis and significantly enhanced the activation of host dendritic cells and antigen cross-presentation through MyD88-dependent pathway, compared to free peptide or the formulation of peptide/CpG mixture. The nanocomplex vaccines effectively migrated into lymph nodes after subcutaneous immunization and elicited strong central and effector memory CD8+ T-cell and Th1 responses. Impressively, immunization with the resulting nanocomplex vaccine in mice led to both advanced protection from B16 tumor challenge and remarkable therapeutic effect against pre-established melanoma tumors. Combining the nanocomplex vaccine with programmed cell death protein 1 (PD1) blockade showed synergistic therapeutic effect for tumors. These findings from three independent epitopes suggest the co-assembly of nanocomplex vaccines may serve as a facile and robust strategy to prepare peptide vaccines without additional delivery platforms including nanoparticles, emulsions, or macroscale hydrogels, thus facilitating the translation of peptide vaccination in cancer immunotherapy.