23:T4de,Prophylactic human papillomavirus (HPV) vaccines are commercially available for prevention of infection with cancerogenic HPV genotypes but are not able to combat pre-existing HPV-associated disease. In this study, we designed a nanomaterial-based therapeutic HPV vaccine, comprising manganese (Mn⁴⁺)-doped silica nanoparticles (Mn⁴⁺-SNPs) and the viral neoantigen peptide GF001 derived from the HPV16 E7 oncoprotein. We show in mice that Mn⁴⁺-SNPs act as self-adjuvants by activating the inflammatory signaling pathway via generation of reactive oxygen species, resulting in immune cell recruitment to the immunization site and dendritic cell maturation. Mn⁴⁺-SNPs further serve as Ag carriers by facilitating endo/lysosomal escape via depletion of protons in acidic endocytic compartments and subsequent Ag delivery to the cytosol for cross-presentation. The Mn⁴⁺-SNPs+GF001 nanovaccine induced strong E7-specific CD8⁺ T cell responses, leading to remission of established murine HPV16 E7-expressing solid TC-1 tumors and E7-expressing transgenic skin grafts. This vaccine construct offers a simple and general strategy for therapeutic HPV and potentially other cancer vaccines.24:T528,The molecular links between sterile inflammation and induction of adaptive immunity have not been fully identified. Here, we examine how damage-associated molecular patterns (DAMPs), as opposed to pathogen-associated molecules (PAMPs), regulate the immune response to non-self-antigens presented at the site of a physical injury. Heat applied briefly to the skin invokes sterile inflammation, characterized by local cell death and caspase-1 activation without demonstrably disrupting skin integrity. Co-delivery of ovalbumin (OVA) with heat injury induces OVA-specific CD8⁺ T-cell responses, and this is dependent on caspase-1 activation and MyD88 signalling. Using Id2flox/flox-CD11cCre+ mice, we demonstrate that CD8⁺ lineage DCs are required to induce OVA-specific CD8⁺ T-cell responses following heat injury. Consistent with this observation, intradermal administration of CD8⁺ lineage DCs but not CD11b⁺ lineage DCs restores priming of CD8⁺ T-cell responses in Casp-1^-/- mice. Thus, we conclude that a sterile injury induces CD8⁺ T-cell immune responses to local antigen through caspase-1 activation and requires CD8⁺ lineage DCs, a finding of significance for immunotherapy and for the pathogenesis of autoimmunity.

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