The antitumor immunity can be enhanced through the synchronized codelivery of antigens and immunostimulatory adjuvants to antigen-presenting cells, particularly dendritic cells (DCs), using nanovaccines (NVs). To study the influence of intracellular vaccine cargo release kinetics on the T cell activating capacities of DCs, we compared stimuli-responsive to nonresponsive polymersome NVs. To do so, we employed "AND gate" multiresponsive (MR) amphiphilic block copolymers that decompose only in response to the combination of chemical cues present in the environment of the intracellular compartments in antigen cross-presenting DCs: low pH and high reactive oxygen species (ROS) levels. After being unmasked by ROS, pH-responsive side chains are exposed and can undergo a charge shift within a relevant pH window of the intracellular compartments in antigen cross-presenting DCs. NVs containing the model antigen Ovalbumin (OVA) and the iNKT cell activating adjuvant α-Galactosylceramide (α-Galcer) were fabricated using microfluidics self-assembly. The MR NVs outperformed the nonresponsive NV in vitro, inducing enhanced classical- and cross-presentation of the OVA by DCs, effectively activating CD8+, CD4+ T cells, and iNKT cells. Interestingly, in vivo, the nonresponsive NVs outperformed the responsive vaccines. These differences in polymersome vaccine performance are likely linked to the kinetics of cargo release, highlighting the crucial chemical requirements for successful cancer nanovaccines.

• MeSH
• adjuvancia imunologická farmakologie   MeSH
• antigeny chemie   MeSH
• CD8-pozitivní T-lymfocyty MeSH
• dendritické buňky MeSH
• koncentrace vodíkových iontů MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nanovakcíny * MeSH
• ovalbumin MeSH
• reaktivní formy kyslíku MeSH
• vakcíny * chemie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• antigeny MeSH
• nanovakcíny * MeSH
• ovalbumin MeSH
• reaktivní formy kyslíku MeSH
• vakcíny * MeSH

Tumor-specific neoantigens can be highly immunogenic, but their identification for each patient and the production of personalized cancer vaccines can be time-consuming and prohibitively expensive. In contrast, tumor-associated antigens are widely expressed and suitable as an off the shelf immunotherapy. Here, we developed a PLGA-based nanoparticle vaccine that contains both the immunogenic cancer germline antigen NY-ESO-1 and an α-GalCer analog IMM60, as a novel iNKT cell agonist and dendritic cell transactivator. Three peptide sequences (85-111, 117-143, and 157-165) derived from immunodominant regions of NY-ESO-1 were selected. These peptides have a wide HLA coverage and were efficiently processed and presented by dendritic cells via various HLA subtypes. Co-delivery of IMM60 enhanced CD4 and CD8 T cell responses and antibody levels against NY-ESO-1 in vivo. Moreover, the nanoparticles have negligible systemic toxicity in high doses, and they could be produced according to GMP guidelines. Together, we demonstrated the feasibility of producing a PLGA-based nanovaccine containing immunogenic peptides and an iNKT cell agonist, that is activating DCs to induce antigen-specific T cell responses.

• Klíčová slova
• B cell epitope, CD4 T cell, CD8 T cell, IMM60, NY-ESO-1, PLGA nanoparticle, iNKT cell, peptide vaccine,
• MeSH
• B-lymfocyty imunologie   MeSH
• CD4-pozitivní T-lymfocyty imunologie   MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• kopolymer kyseliny glykolové a mléčné chemie   farmakologie   MeSH
• lidé MeSH
• nádorové proteiny chemie   farmakologie   MeSH
• nanočástice chemie   terapeutické užití   MeSH
• nosiče léků chemie   farmakologie   MeSH
• peptidové fragmenty chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kopolymer kyseliny glykolové a mléčné MeSH
• nádorové proteiny MeSH
• nosiče léků MeSH
• peptide NY-ESO-1 157-165 MeSH Prohlížeč
• peptidové fragmenty MeSH