Co-delivery of STING and TLR7/8 agonists in antigen-based nanocapsules to dendritic cells enhances CD8+ T cell-mediated melanoma remission
SCHUNKE J. 1, HÜPPE N. 2, GRABBE S. 1, LANDFESTER K. 2, MAILÄNDER V. 1,2, FICHTER M. 1,2
1 Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany; 2 Max Planck Institute for Polymer Research, 55128 Mainz, Germany
Nanocarrier-based antigen delivery is a promising vaccination approach in the context of tumor immunotherapy. Formulating polymeric nanocapsules out of tumor antigens in combination with encapsulated adjuvants enables efficient maturation of antigen-presenting cells, such as dendritic cells, representing a prerequisite for the induction of anti-tumoral immune responses. Thus, NCs composed exclusively of the pharmaceutically active ingredients, i.e. the vaccine antigen as well as the encapsulated resiquimod (R848) in combination with diamidobenzimidazol (diABZI) were synthesized. We demonstrate enhanced activation of DCs by the simultaneous uptake of antigens and adjuvants as well as the induction of subsequent and long-lasting antigen-specific T cell responses in vitro and in vivo by these nanocarriers. In addition, we demonstrated that the combined encapsulation of R848 and diABZI induced stronger anti-tumor immune responses compared to the single adjuvant NC therapies. This was determined by the vigorous expression of CD80, CD83, and CD86. Furthermore, the dual adjuvant therapy initiated the highest secretion levels of IFN-α, IFN-γ, IL-6, and TNF-α. Moreover, a substantial antigen-specific T cell proliferation led to a robust tumor remission in a murine B16 melanoma model. Subcutaneous administration of R848/diABZI-loaded NCs induced enhanced infiltration of CD4+ and CD8+ T cells and neutrophils in tumor-draining lymph nodes and tumor tissue. The encapsulation of a melanoma-specific antigenic peptide of TRP-2 into the adjuvant-loaded NCs reduced the growth of B16 melanoma and prolonged the overall survival. This novel anti-tumor vaccination strategy avoids the use of structural compounds, increases the antigen load of dendritic cells, uses a fixed combination of antigen and two adjuvants and bears the potential to overcome the immunosuppressive tumor microenvironment inducing vigorous antigen-specific anti-cancer immunity.