Targeting Cross-Presentation as a Route to Improve the Efficiency of Peptide-Based Cancer Vaccines

SIMPLE SUMMARY: Cancer vaccination is a potential anti-cancer therapy which may improve clinical outcomes, particularly in combination with current immunotherapies, but to date has demonstrated only limited success. Here we set out to improve the effectiveness of peptide-based cancer vaccine design by implementing a unique approach to target peptide antigens to the cross-presentation pathway within dendritic cells. We demonstrate that the addition of a short cell penetrating peptide sequence to the vaccine construct enhances the efficiency of our vaccine and improves outcomes in both a viral and a cancer model. Our findings provide a simple strategy that may enhance the effectiveness of peptide-based cancer vaccines and the priming of anti-tumor immunity. ABSTRACT: Cross-presenting dendritic cells (DC) offer an attractive target for vaccination due to their unique ability to process exogenous antigens for presentation on MHC class I molecules. Recent reports have established that these DC express unique surface receptors and play a critical role in the initiation of anti-tumor immunity, opening the way for the development of vaccination strategies specifically targeting these cells. This study investigated whether targeting cross-presenting DC by two complementary mechanisms could improve vaccine effectiveness, in both a viral setting and in a murine melanoma model. Our novel vaccine construct contained the XCL1 ligand, to target uptake to XCR1(+) cross-presenting DC, and a cell penetrating peptide (CPP) with endosomal escape properties, to enhance antigen delivery into the cross-presentation pathway. Using a prime-boost regimen, we demonstrated robust expansion of antigen-specific T cells following vaccination with our CPP-linked peptide vaccine and protective immunity against HSV-1 skin infection, where vaccine epitopes were natively expressed by the virus. Additionally, our novel vaccination strategy slowed tumor outgrowth in a B16 murine melanoma model, compared to adjuvant only controls, suggesting antigen-specific anti-tumor immunity was generated following vaccination. These findings suggest that novel strategies to target the antigen cross-presentation pathway in DC may be beneficial for the generation of anti-tumor immunity.